OBJECTIVES: During 2022, Omicron became the dominant SARS-CoV-2 variant in Europe. This study aims to assess the impact of such variant on severe disease from SARS-CoV-2 compared with the Delta variant in Italy. METHODS: Using surveillance data, we assessed the risk of developing severe COVID-19 with Omicron infection compared with Delta in individuals aged ≥12 years using a multilevel negative binomial model adjusting for sex, age, vaccination status, occupation, previous infection, weekly incidence, and geographical area. We also analyzed the interaction between the sequenced variant, age, and vaccination status. RESULTS: We included 21,645 cases of SARS-CoV-2 infection where genome sequencing found Delta (10,728) or Omicron (10,917), diagnosed from November 15, 2021 to February 01, 2022. Overall, 3,021 cases developed severe COVID-19. We found that Omicron cases had a reduced risk of severe COVID-19 compared with Delta cases (incidence rate ratio [IRR] = 0.77; 95% confidence interval [CI]: 0.70-0.86). The largest difference was observed in cases aged 40-59 (IRR = 0.66; 95% CI: 0.55-0.79), while no protective effect was found in those aged 12-39 (IRR = 1.03; 95% CI: 0.79-1.33). Vaccination was associated with a lower risk of developing severe COVID-19 in both variants. CONCLUSION: The Omicron variant is associated with a lower risk of severe COVID-19 compared to infection with the Delta variant, but the degree of protection varies with age.