Background: Reinfections occur as a response to natural infections wanes and novel strains of SARS-CoV-2 emerge. The present research explored the correlation between sex, age, COVID-19 vaccination, prior infection hospitalization, and SARS-CoV-2 reinfection in Sicily, Italy. Materials and Methods: A population-based retrospective cohort study was articulated using the vaccination flux from a regional registry and the Sicilian COVID-19 monitoring system of the Italian Institute of Health. Only adult Sicilians were included in the study, and hazard ratios were calculated using Cox regression. Results: Partial vaccination provided some protection (adj-HR: 0.92), when compared to unvaccinated individuals; furthermore, reinfection risk was reduced by full vaccination (adj-HR: 0.43), and the booster dose (adj-HR: 0.41). Males had a lower risk than females of reinfection with SARS-CoV-2 (adj-HR: 0.75). Reinfection with SARS-CoV-2 was diminished by hospitalization during the first infection (adj-HR: 0.78). Reinfection risk was higher among those aged 30–39 and 40–49 compared to those aged 18–29, whereas those aged 60–69, 70–79, and 80+ were statistically protected. Reinfection was significantly more frequent during the wild-type–Alpha, Delta, Delta–Omicron, and Omicron dominance/codominance waves compared to the wild type. Conclusions: This study establishes a solid base for comprehending the reinfection phenomenon in Sicily by pinpointing the most urgent policy hurdles and identifying some of the major factors. COVID-19 vaccination, one of the most effective public health tools, protects against reinfection, mostly caused by the Omicron strain. Elderly and hospitalized people’s lower risk suggests stricter PPE use.