• Studies conducted in real-world settings allow to address gaps in evidence from clinical trials. • This study evaluates two vaccine brands' effectiveness on the general population. • Comirnaty shows a 81% effectiveness 14 days after the scheduled second dose. • One dose of Vaxzevria showed an effectiveness of 63% after 7 weeks. • These results could help to promote the ongoing vaccination campaign. We estimated the effectiveness of Comirnaty and Vaxzevria vaccines among 371,423 residents in Lazio Region (Italy) vaccinated since 27/12/2020, and followed until diagnosis of SARS-CoV-2 infection or 25/4/2021, whichever came first. By the end of follow-up most of the Comirnaty-cohort (60%) had received the second dose at recommended time of 21 days (98%), while the Vaxzevria-cohort had received only one dose. Adjusted hazard ratios of SARS-CoV-2 infection at weekly intervals since the first dose were estimated through a Cox regression model using 0–13 days as reference time-interval. An increase in effectiveness with increasing time since administration was observed for Comirnaty (five-weeks = 81%, 95 %CI 71–88%; three-months = 94%, 95 %CI 84–98%). One dose of Vaxzevria showed an effectiveness of 63% (95 %CI 25–82%) after 7 weeks, although further analyses are needed after complete vaccination with two doses. These results could support the ongoing vaccination campaign by reinforcing evidence-based communication aimed at reducing vaccine hesitancy. [ABSTRACT FROM AUTHOR]