Beginning the week of December 19-25, 2021, the B.1.1.529 (Omicron) variant of SARS-CoV-2 (the virus that causes COVID-19) became the predominant circulating variant in the United States (i.e., accounted for >50% of sequenced isolates).* Information on the impact that booster or additional doses of COVID-19 vaccines have on preventing hospitalizations during Omicron predominance is limited. Data from the COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) were analyzed to compare COVID-19-associated hospitalization rates among adults aged ≥18 years during B.1.617.2 (Delta; July 1-December 18, 2021) and Omicron (December 19, 2021-January 31, 2022) variant predominance, overall and by race/ethnicity and vaccination status. During the Omicron-predominant period, weekly COVID-19-associated hospitalization rates (hospitalizations per 100,000 adults) peaked at 38.4, compared with 15.5 during Delta predominance. Hospitalizations rates increased among all adults irrespective of vaccination status (unvaccinated, primary series only, or primary series plus a booster or additional dose). Hospitalization rates during peak Omicron circulation (January 2022) among unvaccinated adults remained 12 times the rates among vaccinated adults who received booster or additional doses and four times the rates among adults who received a primary series, but no booster or additional dose. The rate among adults who received a primary series, but no booster or additional dose, was three times the rate among adults who received a booster or additional dose. During the Omicron-predominant period, peak hospitalization rates among non-Hispanic Black (Black) adults were nearly four times the rate of non-Hispanic White (White) adults and was the highest rate observed among any racial and ethnic group during the pandemic. Compared with the Delta-predominant period, the proportion of unvaccinated hospitalized Black adults increased during the Omicron-predominant period. All adults should stay up to date (1) with COVID-19 vaccination to reduce their risk for COVID-19-associated hospitalization. Implementing strategies that result in the equitable receipt of COVID-19 vaccinations, through building vaccine confidence, raising awareness of the benefits of vaccination, and removing barriers to vaccination access among persons with disproportionately higher hospitalizations rates from COVID-19, including Black adults, is an urgent public health priority.