To conduct a nationwide retrospective cohort study to assess trends and hospitalization-associated outcomes in patients with Wernicke encephalopathy. In this nationwide retrospective cohort study, we used in-hospital claims data of patients hospitalized with Wernicke encephalopathy in Switzerland from January 1, 2012, to December 31, 2020. We estimated incidence rates per 100,000 person-years among the overall Swiss population stratified by alcohol and non-alcohol-induced Wernicke encephalopathy. The primary outcome was all-cause in-hospital mortality. Secondary outcomes included progression to Korsakoff syndrome and 1-year hospital readmission. We estimated odds ratios (ORs) for binary outcomes. It was found that 4098 of 4393 hospitalizations (93.3%) for Wernicke encephalopathy during the 8-year study were alcohol-related. Incidence rates for hospitalizations were 14-fold higher in alcohol-related compared with non-alcohol-related Wernicke encephalopathy (5.43 vs 0.39 per 100,000 person-years). The risk for in-hospital mortality was significantly lower in patients with alcohol-related vs non-alcohol-related Wernicke encephalopathy (3.2% vs 8.5%; adjusted OR, 0.38; 95% CI, 0.23 to 0.62). Patients with alcohol-related Wernicke encephalopathy had higher risk for development of Korsakoff syndrome (16.9% vs 1.7%; adjusted OR, 10.64; 95% CI, 4.37 to 25.92) and 1-year hospital readmission (31.6% vs 18.7%; adjusted OR, 1.4; 95% CI, 1.04 to 1.88). In this Swiss nationwide cohort study, Wernicke encephalopathy was a rare but serious cause for hospitalization and mainly alcohol-related. Patients with alcohol-related Wernicke encephalopathy had lower risks of in-hospital mortality but were more likely to develop Korsakoff syndrome and be readmitted to the hospital.