Despite the moderate efficacy of HIV prevention interventions for at risk gay, bisexual, and other men who have sex with men (MSM), MSM continue to represent the largest group of new HIV infections and the largest number of individuals living with HIV in the US. Environmental factors such as sexual minority stress increase the vulnerability of MSM for mental health problems. These mental health problems can be a barrier to consistently engaging in self-care health behaviors such as sexual risk reduction. We consider the following observations critical to identifying priorities for HIV prevention among MSM: (1) gay, bisexual and other MSM have higher rates of mental health problems than general population estimates; (2) these mental health problems co-occur with each other and interact synergistically to increase HIV risk; and (3) comorbid mental health problems may compromise the impact of prevention programs, and integrating treatment of mental health issues into prevention programs may improve program efficacy. Novel prevention interventions for at risk MSM that integrate programming with the treatment of co-occurring and interfering mental health issues are the most promising avenue to increase prevention intervention efficacy and effectiveness. By addressing significant mental health issues and supporting broad based prevention efforts at the individual and community level, there is also the potential to improve the overall quality of life and public mental health of gay, bisexual, and other MSM.