To evaluate the role of sexual behavior stigma as a determinant of depressive symptoms among men who have sex with men (MSM) and transgender women (TGW) in Kigali, Rwanda. MSM/TGW aged ≥18 years were recruited using respondent-driven sampling (RDS) between March-August, 2018. Mental health was assessed using the Patient Health Questionnaire (PHQ-9). Sexual behavior stigma from friends and family, healthcare workers, and community members was assessed using a validated instrument. Multinomial logistic regression models were used to determine the association between sexual behavior stigma and depressive symptoms and depression. Secondary analyses further compared depression and depressive symptoms among MSM and TGW. Among the 736 participants included, 14% (106/736) identified as TGW. Depression 8.9% (RDS-adjusted, 7.6%; 95% CI, 4.6-10.6) and mild/moderate symptoms of depression 26.4% (RDS-adjusted, 24.1%; 95% CI, 19.4-28.7) were common and higher among TGW compared to MSM ( < 0.001). Anticipated (41%), perceived (36%), and enacted (45%) stigmas were highly prevalent, and were also significantly higher among TGW ( < 0.001). In multivariable RDS-adjusted analysis, anticipated (relative risk ratio (RRR), 1.88; 95% CI, 1.11-3.19) and perceived (RRR, 2.06; 95% CI, 1.12-3.79) stigmas were associated with a higher prevalence of depressive symptoms. Anticipated (RRR, 4.78; 95% CI, 1.74-13.13) and enacted (RRR, 3.09; 95% CI, 1.61-5.93) stigmas were also associated with a higher prevalence of depression. In secondary analyses, the significant differences between MSM and TGW were lost after adjusting for stigma. These data demonstrate a high burden of depressive symptoms and depression among MSM/TGW in Kigali. Conceptually, stigma is a likely antecedent of mental health stress among MSM and TGW suggesting the potential utility of scaling up stigma mitigation interventions to improve the quality of life and mental health outcomes among sexual and gender minority communities in Rwanda.