In the US, Latino MSM are disproportionately affected by HIV, yet there is a paucity of data for this risk group. To this end, we examined data on Latino and non-Latino white MSM who participated across six cities in a 2-year randomized behavioral intervention study-Project EXPLORE. At baseline, Latinos reported significantly more serodiscordant unprotected anal intercourse (SDUA) than non-Latinos. Longitudinal predictors of SDUA included marijuana, poppers, amphetamines and heavy drinking, as well as lower self-efficacy, poorer communication skills, weaker safe-sex norms and more enjoyment of risky sex. For HIV infection, Latinos had significantly higher seroconversion rate over follow-up than non-Latinos. Longitudinal predictors of seroconversion among Latinos included poppers and SDUA. Intervention effects did not significantly differ between Latino and non-Latinos. Findings support HIV intervention work with Latino MSM that includes skills training/counseling to address attitudes about safe sex and impact of substance use on HIV-risk behavior and acquisition.