Purpose Heart transplantation (HT) is the preferred and curative treatment for end-stage heart failure. Whether sex affects clinical parameters upon listing to transplantation and/or outcomes after transplantation is not known. Methods 49,200 HT recipients (12,098 [24,6 %] women) enrolled from April 1995 to January 2019 in the Organ Procurement and Transplantation Network (OPTN), were analyzed for sex differences in waiting list characteristics. Analyses were based on OPTN data (June 30, 2019). Multivariable Cox regression was used to identify predictors for sex-specific differences in all-cause mortality, graft failure, cardiac allograft vasculopathy (CAV), and malignancy. Results Upon listing for HT, ischemic cardiomyopathy was more common in men (men 48.2 % vs. 22.2 %, p<0.001), and dilated cardiomyopathy was more common in women (41.3 % vs. 51.6 %, p<0.001). Men showed more diabetes (19.3 % vs. 15.1 %, p<0.001), had more history of smoking (51.1 % vs. 35.8 %, p<0.001), but less frequently a history of malignancy (5.1 % vs. 10.2 %, p<0.001). Men were listed more often as status 1a (46.3 % vs. 40.3 %, p<0.001) and had longer waiting list time (101 vs. 73 days, p<0.001) compared to women. At HT, men were older than women (56 years vs. 53 years, p<0.001). In univariate analysis, mortality (76.6 % vs. 71.8 %, p=0.012), CAV (72 % vs. 68 %, p<0.001) and malignancy (59.1 % vs. 39.4 %, p<0.001) were more common in men than in women. Women showed more graft failure than men (21.8 % vs. 24.6 %, p<0.001). After adjustment for sociodemographic characteristics, differences in mortality and graft failure disappeared. Sex differences persisted for CAV and malignancy (HR 1.21 [1.13, 1.29], p<0.001; and HR 1.80 [1.63, 2.0], p<0.001) even after adjustment for age, sociodemographic factors, ethnicity, education, cardiovascular risk factors, blood group, HLA mismatch, previous malignancy, urgency status, mechanical ventilator, circulatory support, and dialysis. Conclusion In this large-scale registry of HT patients, women and men differed in pre-transplant characteristics and post-transplant outcomes with higher rates of all-cause mortality, CAV and malignancy in men and graft failure in women. Sex differences in CAV and malignancy were not explained by sociodemographic variables, classical risk factors or measures of disease status. Heart transplantation (HT) is the preferred and curative treatment for end-stage heart failure. Whether sex affects clinical parameters upon listing to transplantation and/or outcomes after transplantation is not known. 49,200 HT recipients (12,098 [24,6 %] women) enrolled from April 1995 to January 2019 in the Organ Procurement and Transplantation Network (OPTN), were analyzed for sex differences in waiting list characteristics. Analyses were based on OPTN data (June 30, 2019). Multivariable Cox regression was used to identify predictors for sex-specific differences in all-cause mortality, graft failure, cardiac allograft vasculopathy (CAV), and malignancy. Upon listing for HT, ischemic cardiomyopathy was more common in men (men 48.2 % vs. 22.2 %, p<0.001), and dilated cardiomyopathy was more common in women (41.3 % vs. 51.6 %, p<0.001). Men showed more diabetes (19.3 % vs. 15.1 %, p<0.001), had more history of smoking (51.1 % vs. 35.8 %, p<0.001), but less frequently a history of malignancy (5.1 % vs. 10.2 %, p<0.001). Men were listed more often as status 1a (46.3 % vs. 40.3 %, p<0.001) and had longer waiting list time (101 vs. 73 days, p<0.001) compared to women. At HT, men were older than women (56 years vs. 53 years, p<0.001). In univariate analysis, mortality (76.6 % vs. 71.8 %, p=0.012), CAV (72 % vs. 68 %, p<0.001) and malignancy (59.1 % vs. 39.4 %, p<0.001) were more common in men than in women. Women showed more graft failure than men (21.8 % vs. 24.6 %, p<0.001). After adjustment for sociodemographic characteristics, differences in mortality and graft failure disappeared. Sex differences persisted for CAV and malignancy (HR 1.21 [1.13, 1.29], p<0.001; and HR 1.80 [1.63, 2.0], p<0.001) even after adjustment for age, sociodemographic factors, ethnicity, education, cardiovascular risk factors, blood group, HLA mismatch, previous malignancy, urgency status, mechanical ventilator, circulatory support, and dialysis. In this large-scale registry of HT patients, women and men differed in pre-transplant characteristics and post-transplant outcomes with higher rates of all-cause mortality, CAV and malignancy in men and graft failure in women. Sex differences in CAV and malignancy were not explained by sociodemographic variables, classical risk factors or measures of disease status.