This research examined how family and individual factors influence 3 HIV/AIDS risk behaviors: having more than 1 sexual partner in the last 3 months, substance use at last sexual intercourse, and condom non-use at last sexual intercourse. The sample includes 89 sexually active American Indian adolescents living in a large Southwestern U.S. city. Logistic regression results revealed that family communication acts as a protective factor against HIV risk through a lower reported substance use during last sexual intercourse, but it did not appear to affect the number of multiple recent sex partners. Family and personal involvement in American Indian cultural activities, both low on average in this urban sample, had no effect on outcomes. This study advances knowledge on sexual health risk and protective factors among American Indian adolescents, an understudied group, and provides implications for prevention intervention with American Indian youths and their families.