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Introduction: Globally, depression rates are high among men who have sex with men (MSM). Multiple factors may interact synergistically to increase this risk. This analysis assessed the prevalence of symptoms of depression among MSM in Brazil and synergistic effects of several factors. Methods: Cross-sectional study conducted in 12 cities using respondent-driven sampling. Socio-demographic and behavioral characteristics were collected. The PHQ-9 was used to screen for depression. Having moderate-severe depressive symptoms was compared to none-mild using logistic regression. The syndemic factor was a composite of hazardous alcohol use, sexual violence, and discrimination due to sexual orientation. Those with one to three of these factors were compared to those with none. Results: The weighted prevalence of moderate-severe depressive symptoms was 24.9% (95%CI = 21.8-28.8) and 16.2%, 22.9%, 46.0% and 51.0% when none, one, two, or three syndemic factors were present, respectively, indicating a dose-response effect. Perception of HIV risk, high level of HIV knowledge, known HIV infection, and health self-rated as poor or very poor were also associated with depressive symptoms. Conclusion: The prevalence of moderate-severe depressive symptoms among MSM in Brazil is high, and selected factors act synergistically in increasing their prevalence. Public health policies should consider holistic depression prevention and treatment interventions for this population. [ABSTRACT FROM AUTHOR]