It has been assumed that better HLA matching improves midterm survival in cardiac transplantation. However, statistically reliable data on long-term survival according to HLA matching are scanty. We performed a retrospective analysis of all patients who underwent orthotopic heart transplantation at our heart center between 1989 and 2005. HLA typing data (major histocompatability complex [MHC] class I and II) were available in 923 patients and their heart donors. Univariate and multivariate analyses were performed to assess the impact of HLA matching on long-term survival. The average follow-up period was 6.1 +/- 4.3 years (range, 0.0 to 15.0 years). In total, the 923 patients accrued 5625 patient-years of observation. Zero, one, and two mismatches occurred at each locus in between 0.3% (HLA-B) to 6.6% (HLA-C), 16.6% (HLA-B) to 39.4% (HLA-DQ), and 55.4% (HLA-DQ) to 83.3% (HLA-B), respectively. Two hundred eleven patients died during follow-up (22.9%). Survival at 1, 2, 5, and 10 years was 87.7%, 86.2%, 78.4%, and 63.9%, respectively. In the multivariate analysis, age, transplant era, presence of MHC class I and II antibodies, and high urgency status but not HLA mismatches were independent predictors of long-term survival. Moreover, diagnoses other than dilated cardiomyopathy increased long-term mortality risk. In summary, our data demonstrate that HLA matching is not an independent risk factor for longterm survival in heart transplant recipients. However, several pretransplant factors and transplant era were independently associated with mortality risk.