Objectives: Survival is poor following an orthotopic heart transplant with gender-mismatched donors and recipients. Patients bridged to an orthotopic heart transplant with a ventricular assist device (VAD) frequently become sensitized. We hypothesized that the combination of VAD bridging and gender-mismatch may result in greater rejection and poorer survival. Methods: Data were obtained from the United Network of Organ Sharing database. Patients were divided into 4 groups: (i) VAD recipients who received a heart from a gender-matched donor (VAD-M); (ii) VAD recipients who received a heart from a gender-mismatched donor (VAD-MM); (iii) noVAD recipients who received a heart from a gender-matched donor (noVAD-M); and (iv) noVAD recipients who received a heart from a gender-mismatched donor (noVAD-MM). Rejection episodes within 1-year post-transplant and transplant survival were compared in VAD-M versus VAD-MM and noVAD-M versus noVAD-MM groups, respectively. Results: Between January 2000 and June 2017, of 33 401 adult patients who underwent heart transplants, 8648, 2441, 12 761 and 4992 patients were identified as VAD-M, VAD-MM, noVAD-M and noVAD-MM, respectively. Rejection within 1-year post-transplant occurred in 23.3% and 27.3% of the VAD-M and VAD-MM groups, respectively (P < 0.01) and in 21.8% and 23.6% of the noVAD-M and noVAD-MM groups (P = 0.02), respectively. In an adjusted survival analysis, the VAD-MM group showed significantly worse survival than the VAD-M group (P < 0.01), whereas there was no significant difference between the noVAD-M and noVAD-MM groups (P = 0.21). Conclusions: Our results indicated that the combination of VAD bridging and gender-mismatch caused greater rejection and worse survival following a transplant. Further study is necessary to prove comparable post-transplant survival of gender-matched or -mismatched recipients without VAD bridging.