Abstract Background While overall COVID-19 vaccine uptake is high in the Netherlands, it lags behind in certain subpopulations. Aim We aimed to explore the characteristics of groups with lower COVID-19 vaccine uptake at neighbourhood level to inform the strategy to improve uptake and guide research into barriers for vaccination. Methods We performed an ecological study using national vaccination register and socio-demographic data at neighbourhood level. Using univariate and multivariable generalized additive models we examined the (potentially non-linear) effect of each determinant on uptake. We focused on those aged 50 years and older, since they are at highest risk of severe disease. Results In those over 50 years of age, a higher proportion of individuals with a non-Western migration background and higher voting proportions for right-wing Christian and conservative political parties were at neighbourhood level univariately associated with lower COVID-19 vaccine uptake. In contrast, higher socioeconomic status and higher voting proportions for right-wing liberal, progressive liberal and Christian middle political parties were associated with higher uptake. Multivariable results differed from univariate results in that a higher voting proportion for progressive left-wing political parties was also associated with higher uptake. In addition, with regard to migration background only a Turkish background remained significant. Conclusion We identified determinants associated with COVID-19 vaccine uptake at neighbourhood level and observed heterogeneity in uptake between different subpopulations. Since the goal of vaccination is not only to reduce suffering and death by improving the average uptake, but also to reduce health inequity, it is important to focus on subpopulations with lower uptake.