Moderate to severe psoriasis is often treated with systemic medications, including traditional therapies (eg, methotrexate, cyclosporine) and biologics (eg, TNF inhibitors, IL-17 and IL-23 inhibitors). These immunomodulating treatments raise concerns about infection risks, particularly during the SARS-CoV-2 pandemic. However, literature on systemic therapy and COVID-19 outcomes in the United States is limited. This retrospective cohort study analyzed adults with psoriasis and a primary SARS-CoV-2 diagnosis from the 2020 Health care Cost and Utilization Project National Inpatient Sample database. Patients were stratified by systemic medication use, and propensity score matching adjusted for baseline comorbidities. Logistic regression and bivariate analyses assessed the association between systemic therapy and clinical outcomes, including medications and procedures for COVID-19 treatment, length of stay, and mortality. 721,870 patients were included after propensity score matching. Patients receiving systemic medications had higher odds of requiring supplemental oxygen (OR = 1.30