Background: Patients with psoriasis have multiple risk factors for serious infections, including immune dysregulation, systemic immunosuppressive medications, and comorbid health conditions. Objective: We sought to determine rates and predictors of serious infections in hospitalized psoriasis patients and quantify costs of care, length of stay, and mortality. Methods: We conducted a cross-sectional study of the Nationwide Inpatient Sample from 2002 to 2012, containing a representative 20% sample of all hospitalizations in the United States. Results: In multivariate logistic regression models, psoriasis was associated with multiple serious infections, including methicillin-resistant Staphylococcus aureus (odds ratio [OR] 1.76, 95% confidence intervals [CI] 1.52-2.03), cellulitis (OR 3.21, 95% CI 3.12-3.30), herpes simplex virus infection (OR 2.21, 95% CI 1.70-2.89), infectious arthritis (OR 1.82, 95% CI 1.58-2.09), osteomyelitis (OR 1.31, 95% CI 1.18-1.46), meningitis (OR 1.31, 95% CI 1.16-1.47), encephalitis (OR 1.22, 95% CI 1.02-1.47), and tuberculosis (OR 1.34, 95% CI 1.20-1.49). Among patients with psoriasis, rates of serious infections increased over all time intervals analyzed (P = .01) and were significantly higher compared with those without psoriasis across all time intervals (P < .0001). The mean length of stay (6.6 +/- 0.1 days) and cost of care ($13,291 +/- $166) for psoriasis patients with serious infections was higher than that of psoriasis patients without serious infections (4.6 +/- 0.03 days; $11,003 +/- $96; P < .0001). Limitations: The study was limited to inpatients. Medication data were not available. Conclusion: Serious infections are increasing in incidence in US inpatients with psoriasis.