To evaluate the clinical and imaging characteristics of SARS-CoV-2 breakthrough infection in hospitalized immunocompromised patients in comparison with immunocompetent patients. This retrospective study analyzed consecutive adult patients hospitalized for COVID-19 who received at least one dose of the SARS-CoV-2 vaccine at two academic medical centers between June 2021 and December 2022. Immunocompromised patients (with active solid organ cancer, active hematologic cancer, active immune-mediated inflammatory disease, status post solid organ transplantation, or acquired immune deficiency syndrome) were compared with immunocompetent patients. Multivariable logistic regression analysis was performed to evaluate the effect of immune status on severe clinical outcomes (in-hospital death, mechanical ventilation, or intensive care unit admission), severe radiologic pneumonia (≥ 25% of lung involvement), and typical CT pneumonia. Of 2218 patients (mean age, 69.5 ± 16.1 years), 274 (12.4%), and 1944 (87.6%) were immunocompromised an immunocompetent, respectively. Patients with active solid organ cancer and patients status post solid organ transplantation had significantly higher risks for severe clinical outcomes (adjusted odds ratio = 1.58 95% confidence interval {CI}, 1.01-2.47, = 0.042; and 3.12 95% CI, 1.47-6.60, = 0.003, respectively). Patient status post solid organ transplantation and patients with active hematologic cancer were associated with increased risks for severe pneumonia based on chest radiographs (2.96 95% CI, 1.54-5.67, = 0.001; and 2.87 95% CI, 1.50-5.49, = 0.001, respectively) and for typical CT pneumonia (9.03 95% CI, 2.49-32.66, < 0.001; and 4.18 95% CI, 1.70-10.25, = 0.002, respectively). Immunocompromised patients with COVID-19 breakthrough infection showed an increased risk of severe clinical outcome, severe pneumonia based on chest radiographs, and typical CT pneumonia. In particular, patients status post solid organ transplantation was specifically found to be associated with a higher risk of all three outcomes than hospitalized immunocompetent patients.