The objective of the present article is to identify predictors of willingness to participate (WTP) in microbicide trials among African Americans. A total of 595 participants completed a survey on WTP in microbicide trials and predictors of WTP. Significant associations were observed for relationships of greater WTP with female gender, greater HIV risk, lower mistrust of research, and knowing someone with HIV/AIDS. An interaction revealed HIV risk was positively associated with WTP for women only. Accurate knowledge of the Tuskegee Syphilis Study was associated with greater WTP. These predictors may be employed in microbicide trials to enhance African American participation.