Key Clinical MessageToxoplasmosis‐related huge brain lesions may require decompressive craniectomy and lesion excision to avoid brain damage. In this situation, injectable cotrimoxazole is a better choice for treatment.AbstractToxoplasma gondii is a worldly distributed obligate intracellular protozoa. Toxoplasmosis is a prevalent opportunistic infection in HIV‐infected people, but it was rarely recorded prior to the identification of HIV infection. Here, we report a toxoplasmosis brain lesion in an Iranian HIV‐positive patient. A 45‐year‐old woman with a complaint of malaise was referred to the Valiasr Hospital in Arak city. In her past clinical history, the patient had a history of anemia, deep vein thrombosis (DVT), and positive HIV. The patient was informed of the diagnosis of massive brain toxoplasmosis as a definite diagnosis. The patient was then taken to the operating room for a left decompressive craniectomy, during which the ensuing brain lesion was excised. After a few days, she was discharged from the hospital in good condition and without any complications.