Purpose: This observational study aimed to investigate the incidence of herpes zoster (HZ) among at-risk subjects aged ≥50 years, characterize them and assess annual healthcare utilization and costs from the Italian National Health System (NHS) perspective. Methods: Records of reimbursed drug prescriptions, hospitalizations and outpatient specialist care from the Fondazione ReS database were linked to identify patients aged ≥50 years at HZ risk (i.e. cardiovascular disease/chronic obstructive pulmonary disease/diabetes/immunosuppression, according to the Italian National Vaccine Prevention Plan – PNPV 2017-2019) in 2013. New HZ events (incidence per 1,000) were researched in 2 years, and subjects with HZ in the previous year were excluded. Antiviral and pain therapy consumptions, hospitalizations for HZ and costs paid by NHS were assessed annually. Results: From 12,562,609 inhabitants in 2013, a total of 1,004,705 patients (18.5% aged ≥50 years) at risk without a previous event were selected. The 2-year incidence of HZ was 5.9 per 1,000 (mean age 74 ± 10 years; 54.3% female). Patients aged 80-89 (7.2 per 1,000), females (6.7 per 1,000) and immunosuppressed subjects (6.9 per 1,000) had the highest incidence rates. One year after the new HZ episode, 82.2% were treated with specific antivirals (79.3% brivudine), generating an annual average cost/treated of €106; 8.0% were hospitalized for HZ, with an average cost/hospitalized of €3,927; the overall mean cost/incident patient was €402. Conclusions: This analysis provided HZ incidence in subjects aged ≥50 years considered at risk by the PNPV and its burden from the NHS perspective. Our findings can help health governance to improve clinical decisions and economic positioning concerning zoster vaccine plan.