Purpose: Despite accounting for a minority of malignant pleural mesothelioma (MPM) diagnoses, females may experience differential survival relative to males. It is currently unclear if differences in receipt of treatment between sexes contribute to this survival disparity. We thus utilized the National Cancer Database (NCDB) to assess patterns-of-care and overall survival (OS) in male vs. female patients with MPM. Methods: Patients with histologically-confirmed MPM treated from 2004–2013 were identified from the NCDB. The association between female sex and OS was assessed using multivariable (MV) Cox proportional hazards models with propensity score (PS) matching. Patterns-of-care were assessed using MV logistic regression. The overall treatment effect was tested in subsets of patients by treatment strategy, histology, and clinical stage. Results: A total of 18,799 patients were identified, of whom 14,728 (78%) were male, and 4,071 (22%) were female. Females were more likely to present at a younger age, with less comorbidity, and with epithelioid histology (all p ≤0.001). Despite these favorable prognosticators, females were less likely to receive surgery or chemotherapy compared to males (both p≤0.001). On MV analysis, female sex was associated with improved OS (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.80–0.86, p≤0.001), and this association remained significant following PS-matched MV survival analysis (HR 0.85, 95% CI 0.80-0.89, p≤0.001). This survival disparity was noted across all stages but only in patients with epithelioid histology (p≤0.001). Conclusions: In the largest such analysis to date using a nationally representative contemporary cohort of over 18,000 patients with MPM, we demonstrate that surgery and chemotherapy are disproportionately underutilized in female patients with MPM. Despite this concerning disparity, female sex is independently associated with improved OS relative to males, even when adjusting for potential confounders. The decreased hazard of death associated with female sex appears most pronounced in patients with epithelioid histology, and such an association is more limited or even non-existent in non-epithelioid histologies. As females experience improved OS compared to males with MPM, efforts should be made to reduce disparities in the delivery of potentially life-extending treatments to this population. Further research to understand factors that lead to sex disparities in MPM is warranted.