Healthcare workers (HCWs) played an essential role in managing the COVID-19 pandemic. The Italian Workers’ Compensation Authority (INAIL) and the Italian National Institute of Health (ISS) developed a retrospective study to analyze and understand trends and characteristics of infections among HCWs during the first wave of the pandemic. Between May and September 2020, Italian Regions retrospectively collected anonymous data regarding HCWs infected from the beginning of the pandemic until 30 April 2020 from their administrative sources through a questionnaire asking for socio-demographic and occupational information about the characteristics of contagion and disease outcome. Almost 16,000 valid questionnaires were received. Logistic regression was performed to ascertain the effect of age, gender, geographical macro area, profession, and pre-existing health conditions on the likelihood of HCWs developing more severe forms of COVID-19 (at least hospitalization with mild symptoms). All predictor variables were statistically significant. HCWs at higher risk of developing a more severe disease were males (OR: 1.90; 95% CI: 1.44–2.51), older than 60 years of age (OR: 6.00; 95% CI: 3.30–10.91), doctors (OR: 4.22; 95% CI: 2.22–9.02), working in Lombardy (OR: 55.24; 95% CI: 34.96–87.29) and with pre-existing health conditions (OR: 1.90; 95% CI: 1.43–2.51). This study analyses the main reasons for the overload put on the National Health Service by the first wave of the pandemic and the risk of infection for HCWs by age, gender, occupational profile and pre-existing health conditions. Improved knowledge, availability of personal protective equipment (PPE) and a tight vaccination campaign for HCWs strongly changed the trend of infections among HCWs, with substantial elimination of serious and fatal cases.