Background Limited research has been published on outcomes in heart transplant (HT) recipients with gender-mismatched donors. Objective Compare 3-year post-transplant outcomes in 2 groups of gender-mismatched HT recipients and a no-mismatch group. Methods Sample: 347 HT recipients: 21.3% (74) received a heart from the opposite gender: Group 1: same gender donor/recipient (273, 78.7%); Group 2: female donor/male recipient (40, 11.5%); Group 3: male donor/female recipient (34, 9.8%). Outcomes: mortality, hospitalization, and complications. Results Female patients with male heart donors had shorter 3-year survival, were rehospitalized more days after HT discharge, and had more treated acute rejection episodes and cardiac allograft vasculopathy. No differences were found in: HT length of stay, respiratory failure, stroke, cancer, renal dysfunction, steroid-induced diabetes, number of IV-treated infections, or the timing of infection and rejection. Conclusion Female HT recipients with male donors had worse 3-year outcomes as compared to male-mismatch and no-mismatch groups.