Despite public health campaigns and safer sex messages, many men who have sex with men (MSM) continue to participate in high-risk sexual behaviors, which may make them vulnerable to HIV infection and sexually transmitted infections. The purpose of this study was to determine the relationship of depressive symptoms, self-esteem, and sexual behaviors in a predominantly Hispanic sample of MSM. This correlational study sampled 205 MSM (M = 37 years of age, SD = +/-8) representing the diverse ethnic composition of South Florida. This sample consisted of ethnic minorities (79%) with a large number of foreign-born men (69%). Participants completed measures of depressive symptoms, self-esteem, and sexual behaviors. Results indicated that higher levels of depressive symptoms and higher levels of self-esteem had a statistically significant relationship to lower levels of safer sexual behaviors. Lower income, lower educational level, and preference for Spanish language were associated with higher levels of depressive symptoms; lower income was associated with lower levels of self-esteem; and foreign birth and a preference for Spanish language were associated with lower levels of safer sex behaviors. Higher levels of depressive symptoms and higher levels of self-esteem were associated with high-risk sexual behaviors in this sample of MSM. Further research needs to be directed at culturally specific mental health and HIV prevention strategies for these vulnerable MSM.