From 1966 to 1980 Fraser-Reid was on the faculty of the University of Waterloo in Waterloo, Ontario where he established a research group known as "Fraser-Reid's Rowdies". The primary emphasis of his work at this point was the synthesis of chiral natural products using carbohydrates as the starting materials. In 1975, Fraser-Reid was the first to publish a method for making nonsugar compounds with simple sugars. In 1980, he was hired at the University of Maryland, College Park, and then at Duke University in North Carolina in 1983. In 1985 he was appointed the James B. Duke Professor of Chemistry. At Duke University, his research shifted to exploring the role of oligosaccharides in immune responses, and particularly on the effect of molecules on human diseases like malaria and AIDS. After retiring from Duke in 1996, due to an undisclosed harassment claim, he established the Natural Products & Glycotechnology Research Institute, a nonprofit, to study the carbohydrate chemistry/biology of tropical parasitic diseases in developing countries and to develop a carbohydrate-based malaria vaccine. Fraser-Reid and his team achieved a milestone in oligosaccharide synthesis by assembling a molecule consisting of 28 monosaccharide units.