BACKGROUND: Immunization is an important strategy for controlling the COVID-19 pandemic. COVID-19 vaccination was recently launched in Uganda, with prioritization to healthcare workers and high-risk individuals. In this study, we aimed to determine the acceptability of COVID-19 vaccine among persons at high risk of COVID-19 morbidity and mortality in Uganda. METHODS: Between 29 March and 14 April 2021, we conducted a cross-sectional survey consecutively recruiting persons at high risk of severe COVID-19 (diabetes mellitus, HIV and cardiovascular disease) attending Kiruddu National Referral Hospital outpatient clinics. A trained research nurse administered a semi-structured questionnaire assessing demographics, COVID-19 vaccine related attitudes and acceptability. Descriptive statistics, bivariate and multivariable analyses were performed using STATA 16. RESULTS: A total of 317 participants with a mean age 51.5 ± 14.1 years were recruited. Of this, 184 (60.5%) were female. Overall, 216 (70.1%) participants were willing to accept the COVID-19 vaccine. The odds of willingness to accept COVID-19 vaccination were four times greater if a participant was male compared with if a participant was female [adjusted odds ratio (AOR): 4.1, 95% confidence interval (CI): 1.8-9.4, p = 0.00]. Participants who agreed (AOR: 0.04, 95% CI: 0.01-0.38, p = 0.003) or strongly agreed (AOR: 0.04, 95% CI: 0.01-0.59, p = 0.005) that they have some immunity against COVID-19 were also significantly less likely to accept the vaccine. Participants who had a history of vaccination hesitancy for their children were also significantly less likely to accept the COVID-19 vaccine (AOR: 0.1, 95% CI: 0.01-0.58, p = 0.016). CONCLUSION: The willingness to receive a COVID-19 vaccine in this group of high-risk individuals was comparable to the global COVID-19 vaccine acceptance rate. Increased sensitization, myth busting and utilization of opinion leaders to encourage vaccine acceptability is recommended.