Aim To evaluate the clinical characteristics of adult and adolescent Croatian patients hospitalized for herpes zoster over a period of 21 years in the largest national center for infectious diseases (catchment area approximately 25% of the Croatian population). Methods This retrospective chart review included all patients older than 15 years hospitalized for herpes zoster at the University Hospital for Infectious Diseases “Dr. Fran Mihaljević” between January 1, 1996 and December 31, 2016. Results The study enrolled 1755 patients (uniform annual hospitalizations), 50% of whom suffered from complicated forms of herpes zoster, mostly generalized zoster (22.0%), infected lesions (14.8%), and meningitis/encephalitis (10.4%). A low percentage of patients experienced Ramsey-Hunt syndrome (3.0%), keratitis (1.5%), and visceral dissemination (0.2%). The majority of patients were older than 55 years (80%, median 70 years). Overall, 61.6% of patients suffered from at least one comorbidity (most frequent: diabetes 14.6%, cardiovascular incidents 24.4%, malignancy 13.0%, other infection 12.9%), and 28.2% suffered from ≥2 comorbidities. All-cause in-hospital mortality was 0.9%. The proportion of patients with any complicated form and of patients with meningitis/encephalitis steadily decreased over time, while the proportion of patients with comorbidities increased. This coincided also with steadily increasing age. No association was observed between comorbidities and complicated forms of zoster. Pharmacological immunosuppression was associated with generalized zoster; younger age was associated with meningitis/encephalitis; and older age was associated with generalized zoster and infected lesions. Conclusion The patients most frequently hospitalized for herpes zoster are elderly people burdened with comorbidities, not necessarily patients with complicated forms of the disease.