Male clients of female sex workers (FSWs) may act as a bridge to the general population contributing to the spread of HIV and other sexually transmitted infections (STIs) in the USA and Mexico. This study used cross-sectional data to identify psychosexual and social-cognitive factors associated with sexual risk behavior in a bi-national sample of 300 male clients of FSWs recruited in Tijuana, Mexico from June to October 2008. In a multiple regression analysis, the number of unprotected vaginal sex acts with FSWs was associated with higher sexual compulsivity scores, lower self-efficacy for condom use, greater use of illicit drugs, and more financial need. Behavioral interventions are urgently needed to assist clients of FSWs in reducing high-risk behaviors in an effort to prevent the spread of HIV/STIs in this high-risk population and their sexual partners.