The global prevalence of HIV is notably higher in men who have sex with men (MSM) compared with other male populations. Unprotected anal intercourse is the riskiest sexual behavior for HIV acquisition and/or transmission among this minority population. The purpose of the study was to identify if the syndemic of psychosocial stressors and experienced stigma are predictors of unprotected anal sex in Mexican MSM. A cross-sectional analytic study was carried out. It included adults residing in Manzanillo, Mexico, with oral/anal sex practices within the last year. Informed consent was given by 142 participants selected using snowball sampling. Collected data included sociodemographic characteristics, psychosocial stressors, experienced stigma, HIV knowledge, knowing a friend/acquaintance living with HIV/AIDS, and sexual risk behaviors. Adjusted logistic regression was used to identify predictors of unprotected anal sex within the last six months. Presence of syndemic of psychosocial stressors, drug use during sex, having friends/acquaintances with HIV/AIDS, and experiencing high stigma were positively associated; high level of HIV knowledge was negatively linked. Reducing psychosocial stressors and integrating stigma-mitigation strategies are key elements to reduce HIV transmission.