Introduction: The COVID-19 pandemic and its control measures have impacted health and healthcare provision in various levels. Physical distancing measures, for instance, may affect sexual health, impacting access to HIV prevention supplies and changing sexual behaviour, as well as mental health, increasing feelings of unsafety and weakening community support ties. These effects can be worsened among socially marginalised groups, such as men who have sex with men (MSM) and transgender women (TGW). Brazil is among the countries most affected by COVID-19 in the world, where control measures have been inconsistently implemented. We aim to investigate the effects of the COVID-19 pandemic on the sexual and mental health of adolescent and adult MSM and TGW in Brazil. Methods: Convergent mixed-method prospective cohort study, nested in two ongoing HIV pre-exposure prophylaxis (PrEP) cohorts in Brazil, named PrEP1519 and Combina. Participants will be invited to answer, at baseline and after 6months, a questionnaire about the effects of the COVID-19 pandemic on sexual behaviour, HIV prevention and mental health. Data on HIV infection and sexually transmitted infections (STI) will be collected as part of routine follow-up from the cohorts. Main outcome measures (HIV infection, STI and depression symptoms) will be observed within 12 months after baseline. Sample size is estimated at 426 participants. Complementarily, 50 participants will be invited to in-depth interviews through video calls or interactive voice response, and 20 will be invited to chronicle their lives during the pandemic through digital diaries. Triangulation will be done across qualitative methods and with the quantitative data. Ethics and dissemination: The study was approved by Research Ethics Committees from the Brazilian Universities coordinating the study. Findings will be published in scientific journals and presented at meetings. Informative flyers will be elaborated to communicate study findings to participants and key stakeholders.