Background The purpose of this study was to estimate the relationship of age, race and gender to rejection and infection across time with respect to age at time of transplant, year of transplantation and immunosuppressive era. Methods The study group consisted of 10,131 patients from 29 institutions in the Cardiac Transplant Research Database (n = 7,368, from 1990 to 2008) and 32 institutions in the Pediatric Heart Transplant Study (n = 2,763, from 1993 to 2008). The probabilities of rejection death and infection death were estimated with a parametric time-related model and adjusted for gender, ethnicity, date of transplant and age. Results Actuarial survival by age at transplant showed that, when compared with the majority of patients transplanted between the ages of 30 to 60 years, death due to rejection at 5 years was highest among those transplanted at 10 to 30 years of age (p < 0.0001) and lowest in those transplanted at >60 years of age. Death due to infection at 5 years was highest among patients >60 years of age. Risk factors for death from rejection included age (p < 0.0001), female gender (p = 0.0001), black race (p < 0.0001) and transplant date (p < 0.0001); for infection death, risk factors were age (p < 0.0001), date of transplant (p < 0.0001), age (p = 0.002) and black race (p = 0.01). Modeling with respect to age at time of transplant showed an inverse relationship between infection and rejection death. Among patients transplanted at >60 years of age, there was a steep increase in infection-related deaths and a decrease in rejection deaths. Risk for rejection was elevated among young adults 10 to 30 years of age at time of transplant, particularly for black females. Conclusion Death from rejection affects adolescents and young adults preferentially, especially black recipients, whereas death from infection preferentially affects patients >60 years of age. Relative risk of infection vs rejection death with respect to recipient age should be considered in therapeutic plans for recurrent rejection, particularly in adolescents and the elderly. © 2011 International Society for Heart and Lung Transplantation.