Background Few reports have evaluated the effect of the SARS-CoV-2 variant and vaccination on the clinical and imaging features of COVID-19. Purpose To evaluate and compare the effect of vaccination and variant prevalence on the clinical and imaging features of infections by the SARS-CoV-2. Materials and Methods Consecutive adults hospitalized for confirmed COVID-19 at three centers (two academic medical centers and one community hospital) and registered in a nationwide open data repository for COVID-19 between August 2021 and March 2022 were retrospectively included. All patients had available chest radiographs or CT images. Patients were divided into two groups according to predominant variant type over the study period. Differences between clinical and imaging features were analyzed with use of the Pearson χ2 test, Fisher exact test, or the independent t test. Multivariable logistic regression analyses were used to evaluate the effect of variant predominance and vaccination status on imaging features of pneumonia and clinical severity. Results Of the 2180 patients (mean age, 57 years ± 21; 1171 women), 1022 patients (47%) were treated during the Delta variant predominant period and 1158 (53%) during the Omicron period. The Omicron variant prevalence was associated with lower pneumonia severity based on CT scores (odds ratio [OR], 0.71 [95% CI: 0.51, 0.99; P = .04]) and lower clinical severity based on intensive care unit (ICU) admission or in-hospital death (OR, 0.43 [95% CI: 0.24, 0.77; P = .004]) than the Delta variant prevalence. Vaccination was associated with the lowest odds of severe pneumonia based on CT scores (OR, 0.05 [95% CI: 0.03, 0.13; P < .001]) and clinical severity based on ICU admission or in-hospital death (OR, 0.15 [95% CI: 0.07, 0.31; P < .001]) relative to no vaccination. Conclusion The SARS-CoV-2 Omicron variant prevalence and vaccination were associated with better clinical outcomes and lower severe pneumonia risk relative to Delta variant prevalence. © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Little in this issue.