Due to the COVID-19 pandemic, all countries with a global mobilization started to produce and authorize vaccines, prioritizing healthcare professionals (HCPs) to reduce transmission. The aim of this study was to assess post-vaccination infections’ occurrence among HCPs and their correlation with symptom onset. A retrospective cohort study was carried out in the Campania Region from December 2020 to April 2021. Data were retrieved from the Regional Health Information System of the Campania Region (Sinfonia). The study cohort included subjects that had all received at least one vaccine dose. Risk ratios (RRs) adjusted for age and sex (95% confidence intervals) were performed to assess differences in the prevalence between HCPs who tested positive or negative for COVID-19. Univariate and multivariate logistic regression models were used to evaluate the association between symptoms and vaccination status. Findings revealed that HCPs had a lower risk of contracting COVID-19 after receiving at least one vaccine dose, and this risk decreased with age. Furthermore, not having full vaccination coverage may predict a severe/critical evolution of the disease. This study provides a snapshot of the initial state of the Italian vaccination campaign on HCPs. A surveillance approach using Big Data matched to clinical conditions could offer a real analysis in the categorization of subjects most at risk.