The prevalence of anti-SARS-CoV-2 antibodies and potential determinants were assessed in a random sample representative of the Belgian adult population. In total, 14,201 individuals (≥18 years) were invited by mail to provide saliva via an Oracol® swab. Survey weights were applied, and potential determinants were estimated using multivariable logistic regressions. Between March and August 2021, 2767 individuals participated in the first data collection. During this period, which coincided with the onset of the vaccination campaign, the seroprevalence in the population increased from 25.2% in March/April to 78.1% in July. Among the vaccinated there was an increase from 74,2% to 98.8%; among the unvaccinated, the seroprevalence remained stable (around 17%). Among the vaccinated, factors significantly associated with the presence of antibodies were: having at least one chronic disease (ORa 0.22 (95% CI 0.08–0.62)), having received an mRNA-type vaccine (ORa 5.38 (95% CI 1.72–16.80)), and having received an influenza vaccine in 2020–2021 (ORa 3.79 (95% CI 1.30–11.07)). Among the unvaccinated, having a non-O blood type (ORa 2.00 (95% CI 1.09–3.67)) and having one or more positive COVID-19 tests (ORa 11.04 (95% CI 4.69–26.02)) were significantly associated. This study provides a better understanding of vaccine- and/or natural-induced presence of anti-SARS-CoV-2 antibodies and factors that are associated with this presence.