The only difference between in spite of and despite is the ‘of’.
You don't use "Despite of the reason ".
You use "Despite the reason " Despite the pain in his leg he completed the marathon.
It seems to me "in spite of" is a slightly more elaborate form, to be used in more fancy, most formal writing. "
Despite" is not informal but not quite that elaborate.
edit: as mcalex mentions, "Despite of" (and even "In despite of") is not incorrect, it's just an almost dead archaic form .
ell.stackexchange.com/users/30/SF.
"despite" and "in spite of" are synonyms.
As per this reference from Lawless English : "Despite" means "even though," "notwithstanding," or "regardless of.
" It's the opposite of "because of/due to," and can be used with a noun or gerund.
She had difficulty communicating in French despite all her years of study.
We lost the game, despite the fact that we practiced all week.
Despite not having an umbrella, I walked home in the rain.
"
In spite of" means exactly the same thing and is used exactly the same way as "despite."
She had difficulty communicating in French in spite of all her years of study.
We lost the game, in spite of the fact that we practiced all week.
In spite of not having an umbrella, I walked home in the rain.
So, they can safely be used interchangeably.
You may notice that in all the above examples, "despite" has not been used with "of" but it can definitely be used in certain contexts such as this: A large number of ladies, both from this City and abroad, who had come out, despite of the driving rain-storm, were in attendance, and occupied seats in the galleries.
And again here, it is absolutely interchangeable with "in spite of".
ell.stackexchange.com/users/92/Mohit
To me, while they, in many cases, can be used interchangeably, the choice of wording can imply a subtle shift in meaning.
In spite of has the connotation of doing something with a bit of rebellion or desire to irritate as a motivation.
spite : Ill will or hatred toward another, accompanied with the disposition to irritate, annoy, or thwart; a desire to vex or injure; petty malice; grudge; rancor.
So I would use in spite of in a case like: "
I went downtown to the party in spite of my parents' warning that it wasn't safe.
"
In other words, use in spite of when your attitude is: Warning be damned, I'm doing it anyway.
I thumb my nose at your so-called warning.
Despite doesn't seem to have that same desire to irritate or be contrary behind it, and can be used when an action is taken that may fly in the face of information which would argue against it.
So I would use despite in a case where I wanted to emphasize the decision rather than the motivation behind it.
If I said instead, "I went downtown despite my parents' warning that it wasn't safe.
" I would be saying that I considered my parents' advice but concluded that either the risk was worth it, or that the risk was overstated or that the three friends I was going with were big enough to protect me, etc.
ell.stackexchange.com/users/147/Jim
This has been covered in an EL&U question , which pertains more specifically to the sytax of the two, rather than the difference.
Basically, they mean the same (both options have been suggested as being the more 'formal'), and general usage says you should only use 'in spite of', or 'despite' (but not 'despite of').
However, the 'despite of' usage is not illegal, though it is fairly rare, and as they suggest in the EL&U answer, something that you only bring up when you get caught out doing it accidentally.
ell.stackexchange.com/users/89/mcalex
I do agree that the two; 'despite' and 'in spite of', are "interchangeable'.
However, the "subtle distinction" mentioned earlier, in itself, makes it a matter of fact that they are not the same because not even the word 'interchangeable" means "the same". '
in spite of', suggests a connotation to a degree of contempt or rebellion.
Where as, 'Despite' is usually more of a neutral contradiction within a circumstance.
Examples of proper usage: "I'm going to marry him in spite of his extensive criminal record.
" "Due to his extensive criminal record, we will not employ him despite his impressive resume.
"or simply: "I will not marry her despite the children we have together."
"I will marry him in spite of the amount of times he cheated" 'in spite of' is a preposition to be used in front of a negative instancesand 'despite' is used when contradicting a positive instance.
These ought not be confused with the infinitive verb "to spite", which is meant as a direct rebellion: "I punched him in the face to spite him."
ell.stackexchange.com/users/8729/Swanful
I think the two words can be used interchangeably depending on the messege the user intend to send; the 'verb' here connotes the "power" of any fo the two.
Spite could mean rebellion in real sense but could also connote courage or boldness depending on the usage
ell.stackexchange.com/users/10916/Akila Bulus
What are the difference between these two prepositions: "despite of" and "in spite of"?  And what is the general usage of this two: choose in different situation, followed by etc.
Usage "in spite of" and "despite of"
ell.stackexchange.com
<difference><phrase-usage>
ell.stackexchange.com/questions/506
ell.stackexchange.com/users/None/
 "Despite" and "in spite of", are synonyms and are interchangeable.  However, some argue that "in spite of", suggests a degree of contempt or rebellion, whereas "despite" is more neutral. The two are subtly different. 'In spite of' is more elaborate and implies rebellion whilst 'despite' is more neutral and circumstancial.
The two can be used interchangeably and are subtly different. In spite of' is more elaborate and implies rebellion. Despite' is more neutral and circumstancial.