BACKGROUND: Effective condom use is a critical intervention to limit the spread of HIV and other sexually transmitted infections, particularly among individuals in high-risk networks who practice anal sex. We characterized condom failures in cisgender men who have sex with men and transgender women in Nigeria. SETTING: The TRUST/RV368 cohort provided condoms, compatible lubricants, and safer sex education to men who have sex with men and transgender women at community-engaged health centers in Abuja and Lagos, Nigeria. METHODS: Participants completed structured interview questions about condom usage and failure every 3-6 months. Robust Poisson regression models with generalized estimating equations were used to estimate relative risks and 95% confidence intervals for prespecified factors potentially associated with condom failure in the previous month. RESULTS: From September 2013 to September 2019, 2221 of 2737 participants (81.1%) reported condom use for anal sex with a male partner in the last month, and 305 (13.7%) reported condom failure during this time. Multivariate analyses demonstrated an increased risk of condom failure at postenrollment visits, as well as in participants who reported frequent Internet use, 2 or more casual sexual partners, and 2-4 main sexual partners. Those who cohabited with a woman had reduced risk. CONCLUSIONS: Condom failure was common in this population despite freely available condoms, compatible lubrication, and education. Increased risk of condom failure over time could reflect message fatigue a ceiling for effective condom use, or new uptake of condoms by inexperienced users.