Abstract Purpose We aimed to assess the seroprevalence trends of SARS-CoV-2 antibodies in several Swiss cantons between May 2020 and September 2021 and investigate risk factors for seropositivity and their changes over time. Methods We conducted repeated population-based serological studies in different Swiss regions using a common methodology. We defined three study periods: May–October 2020 (period 1, prior to vaccination), November 2020–mid-May 2021 (period 2, first months of the vaccination campaign), and mid-May–September 2021 (period 3, a large share of the population vaccinated). We measured anti-spike IgG. Participants provided information on sociodemographic and socioeconomic characteristics, health status, and adherence to preventive measures. We estimated seroprevalence with a Bayesian logistic regression model and the association between risk factors and seropositivity with Poisson models. Results We included 13,291 participants aged 20 and older from 11 Swiss cantons. Seroprevalence was 3.7% (95% CI 2.1–4.9) in period 1, 16.2% (95% CI 14.4–17.5) in period 2, and 72.0% (95% CI 70.3–73.8) in period 3, with regional variations. In period 1, younger age (20–64) was the only factor associated with higher seropositivity. In period 3, being aged ≥ 65 years, with a high income, retired, overweight or obese or with other comorbidities, was associated with higher seropositivity. These associations disappeared after adjusting for vaccination status. Seropositivity was lower in participants with lower adherence to preventive measures, due to a lower vaccination uptake. Conclusions Seroprevalence sharply increased over time, also thanks to vaccination, with some regional variations. After the vaccination campaign, no differences between subgroups were observed.