Background Recent studies have identified important social inequalities in SARS-CoV-2 infections and related COVID-19 outcomes in the Belgian population. The aim of our study was to investigate the sociodemographic and socioeconomic characteristics associated with the uptake of COVID-19 vaccine in Belgium. Methods We conducted a cross-sectional analysis of the uptake of a first COVID-19 vaccine dose among 5 342 110 adults (≥18 years) in Belgium on 31 August 2021. We integrated data from four national data sources: the Belgian vaccine register (vaccination status), COVID-19 Healthdata (laboratory test results), DEMOBEL (sociodemographic/socioeconomic data) and the Common Base Register for HealthCare Actors (individuals licensed to practice a healthcare profession in Belgium). We used multivariable logistic regression analysis for identifying characteristics associated with not having obtained a first COVID-19 vaccine dose in Belgium and for each of its three regions (Flanders, Brussels and Wallonia). Results During the study period, 10% (536 716/5 342 110) of the Belgian adult population included in our study sample was not vaccinated with a first COVID-19 vaccine dose. A lower COVID-19 vaccine uptake was found among young individuals, men, migrants, single parents, one-person households and disadvantaged socioeconomic groups (with lower levels of income and education, unemployed). Overall, the sociodemographic and socioeconomic disparities were comparable for all regions. Conclusions The identification of sociodemographic and socioeconomic disparities in COVID-19 vaccination uptake is critical to develop strategies guaranteeing a more equitable vaccination coverage of the Belgian adult population.