Exogenous estrogen is associated with reduced COVID mortality in non-immunosuppressed/immunocompromised (non-ISC) post-menopausal females. Here, we examined the association of estrogen or testosterone hormone replacement therapy (HRT) with COVID outcomes in solid organ transplant recipients (SOTR) compared to non-ISC individuals, given known differences in sex-based risk in these populations. SOTR >45y with COVID-19 between 04-01-2020 and 07-31-2022 were identified using the National COVID Cohort Collaborative. The association of HRT use in the last 24 months (exogenous systemic estrogens for females; testosterone for males) with major adverse renal or cardiac events (MARCE) in the 90-days post COVID diagnosis and other secondary outcomes were examined using multivariable cox proportional hazards models and logistic regression. We repeated these analyses in a non-ISC control group for comparison. Our study included 1,135 SOTR and 43,383 immunocompetent patients on HRT with COVID-19. In non-ISC, HRT use was associated with lower risk of MARCE (aHR 0.61, 95% CI 0.57-0.65 for females; aHR 0.70, 0.65-0.77 for males), and all secondary outcomes. In SOTR, HRT reduced the risk of AKI (aHR 0.79, 0.63-0.98) and mortality (aHR 0.49, 0.28-0.85) in males with COVID, but not in females. The potentially modifying effects of immunosuppression on the benefits of HRT requires further investigation.