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IMPORTANCE: Understanding risk factors for hospitalization in vaccinated persons and the association of COVID-19 vaccines with hospitalization rates is critical for public health efforts to control COVID-19. OBJECTIVE: To determine characteristics of COVID-19–associated hospitalizations among vaccinated persons and comparative hospitalization rates in unvaccinated and vaccinated persons. DESIGN, SETTING, AND PARTICIPANTS: From January 1, 2021, to April 30, 2022, patients 18 years or older with laboratory-confirmed SARS-CoV-2 infection were identified from more than 250 hospitals in the population-based COVID-19–Associated Hospitalization Surveillance Network. State immunization information system data were linked to cases, and the vaccination coverage data of the defined catchment population were used to compare hospitalization rates in unvaccinated and vaccinated individuals. Vaccinated and unvaccinated patient characteristics were compared in a representative sample with detailed medical record review; unweighted case counts and weighted percentages were calculated. EXPOSURES: Laboratory-confirmed COVID-19–associated hospitalization, defined as a positive SARS-CoV-2 test result within 14 days before or during hospitalization. MAIN OUTCOMES AND MEASURES: COVID-19–associated hospitalization rates among vaccinated vs unvaccinated persons and factors associated with COVID-19–associated hospitalization in vaccinated persons were assessed. RESULTS: Using representative data from 192 509 hospitalizations (see Table 1 for demographic information), monthly COVID-19–associated hospitalization rates ranged from 3.5 times to 17.7 times higher in unvaccinated persons than vaccinated persons regardless of booster dose status. From January to April 2022, when the Omicron variant was predominant, hospitalization rates were 10.5 times higher in unvaccinated persons and 2.5 times higher in vaccinated persons with no booster dose, respectively, compared with those who had received a booster dose. Among sampled cases, vaccinated hospitalized patients with COVID-19 were older than those who were unvaccinated (median [IQR] age, 70 [58-80] years vs 58 [46-70] years, respectively; P < .001) and more likely to have 3 or more underlying medical conditions (1926 [77.8%] vs 4124 [51.6%], respectively; P < .001). CONCLUSIONS AND RELEVANCE: In this cross-sectional study of US adults hospitalized with COVID-19, unvaccinated adults were more likely to be hospitalized compared with vaccinated adults; hospitalization rates were lowest in those who had received a booster dose. Hospitalized vaccinated persons were older and more likely to have 3 or more underlying medical conditions and be long-term care facility residents compared with hospitalized unvaccinated persons. The study results suggest that clinicians and public health practitioners should continue to promote vaccination with all recommended doses for eligible persons.