The aim of this study was to investigate the spatio-temporal association between socio-economic deprivation and the incidence of COVID-19 and how this association changes through the seasons and due to the existence of restrictive public health measures. A retrospective observational study was conducted among COVID-19 cases that occurred in the Apulia region from 29 February 2020 to 31 December 2021, dividing the period into four phases with different levels of restrictions. A generalized estimating equations model was applied to test the independent effect of deprivation on the incidence rate of COVID-19, taking into account age, sex, and regional incidence rate as possible confounding effects and covariates such as season and levels of restrictions as possible modifying effects. The highest incidence rate was in areas with a Very High deprivation Index (DI) in winter (107.2 for 100,000 ab. ± 7.5), while in autumn, the highest Rate Ratio (RR) was estimated between Very High vs. Low DI (3.83, p<.001). During total lockdown, no RR between areas with different levels of DI was significant, while during soft lockdown, areas with Very High DI were more at risk than all other areas. The effects of social inequalities on incidence rate of COVID-19 change in as-sociation with the seasons and restrictions on public health. Disadvantaged areas showed a higher incidence rate of COVID-19 in the cold seasons and in the phases of soft lockdown.