Importance In light of the COVID-19 epidemic in Belgium, knowledge on the susceptibility to SARS-CoV-2 and its evolution over time, related to control measures that have been taken, is tremendously important to guide policy makers aiming to control the epidemic wave. Objective To assess the evolving seroprevalence and seroincidence with regards to a national lock-down in Belgium. Design, setting and participants In this prospective serial cross-sectional nationwide seroprevalence study, stratified by age, sex and region, 3000-4000 residual samples were collected in each of five collection periods during and after national lockdown between 30 March and 5 July 2020. Residual sera from outside hospitals were randomly selected by diagnostic laboratories and analyzed for IgG antibodies against S1 proteins of SARS-CoV-2 with a semi-quantitative commercial ELISA. Seropositivity (overall, by age category and sex) and seroincidence over 3 to 4 week periods were estimated for the Belgian population. Exposure Recent exposure to SARS-CoV-2 was estimated in the Belgian population. Main outcomes and measures The primary study outcomes were the weighted seroprevalence and seroincidence against SARS-CoV-2 in the Belgian population during five consecutive periods in Belgium. Results The weighted overall seroprevalence initially increased from 2.9% (95% CI 2.3 to 3.6) to 6.0% (95% CI 5.1 to 7.1), implying a seroincidence of 3.1% (95% CI 1.9 to 4.3) between the 1st and 2nd collection period. Thereafter, seroprevalence stabilized and decreased from the 3rd to 5th period from 6.9% (95% CI 5.9 to 8.0) to 4.5% (95% CI 3.7 to 5.4). Conclusions and relevance During lockdown, an initial small but increasing fraction of the Belgian population showed serologically detectable signs of exposure to SARS-CoV-2, which did not further increase when confinement measures eased and full lockdown was lifted. In combination with the reported COVID-19 cases in Belgium, the estimated seroprevalences reported in this study may have helped to calibrate the Belgian response to the epidemic's first wave and to guide policy makers to control for potential future waves. Seroprevalence estimates indicate that we are far from herd-immunity. Moreover, more research is needed to confirm if seropositivity correlates to protective immunity against the virus.