Objective: Human Immunodeficiency Virus (HIV) Key Populations (KPs) include Female Sex Workers (FSWs), men who have sex with men (MSM), transgender (TG), and transsexual (TS) persons. This study assessed coronavirus disease 2019 (COVID-19) vaccine uptake among KPs for HIV in India, adverse events following immunization (AEFI), and breakthrough infections among the vaccinated.Materials and Methods: This retrospective cohort study was conducted among 421 KPs enrolled in 41 Targeted Intervention (TI) clusters in 31 districts of the Tamil Nadu State Acquired Immunodeficiency Syndrome (AIDS) Control Society (TANSACS), India, from June to September 2022. A semi-structured, bilingual (English and Tamil), interviewer-administered questionnaire was used to collect data on socio-demographic characteristics, vaccination status, AEFIs, and breakthrough infections among the KPs under the TIs.Results: Among the KPs, 45.4% were FSWs, 37.1% were MSM, 16.2% were TG, and 1.4% were TS persons. Among them, 4.3% had HIV, and 2.9% had syphilis or other sexually transmitted infections (STIs). The COVID-19 vaccine uptake rate was 96%. Among the KPs, TG/TS persons had the highest vaccine uptake (98.6%), followed by FSWs (96.3%) and MSM (94.2%). AEFIs were reported by 85.4% of the participants. HIV positive status was significantly associated with the incidence of AEFI. The breakthrough infection rate was 5.4% among the vaccinated participants.Conclusion: The COVID-19 vaccine uptake among HIV KPs was high in Tamil Nadu. AEFIs and breakthrough infections among COVID-19 vaccinated HIV KPs may be low, with mild AEFIs.