Abstract Background Evidence suggests that people from lower socioeconomic status are at higher risk of infectious disease impact, owed to virus exposure, susceptibility and incomplete or delayed vaccination. However, It is unknown whether COVID-19 incidence disparities is due to social inequalities or social vaccination inequalities. The aim of this research is to determine whether socioeconomic characteristics are associated with COVID-19 infections in Belgium by measuring its direct effect, and to quantify the indirect role of socioeconomic determinants on COVID-19 infections by examining the role of vaccination as a mediator in this association. Methods In this retrospective cohort, all patients tested for COVID-19, at least once, in Belgium between 1 September 2021 and 1 September 2022 will be included in our analysis. A survival analysis will be conducted to compare time to the endpoint defined as COVID-19 infection according to socioeconomic characteristics. Mediation analysis for vaccination status will be conducted to assess the role of vaccination in the association between socioeconomic factors and COVID-19 infection. Results Expected results would give us an understanding of the impact of socioeconomic characteristics on COVID-19 infections in Belgium using on a population-based approach and considering the mediating effect of vaccination. Conclusions Mediation analysis is a novel approach for better understanding virus exposure and susceptibility in a context marked by socioeconomic inequalities. Understanding these patterns will allow better health-system preparedness for future pandemics. Key messages • Understanding social inequalities is essential for better health-system preparedness and response. • Mediation analysis allows to understand the direct effect of socioeconomic inequalities on COVID-19 infections and the indirect effect mediated through vaccination.