BACKGROUND: Rejection is a major cause of morbidity and mortality after pediatric heart transplantation (HTx). Survival after pediatric HTx has improved over time, but whether there has been an era-related improvement in the occurrence of allograft rejection is unknown. METHODS: The Pediatric Heart Transplant Study (PHTS) database was queried for patients who underwent HTx from January 1993 to December 2005 to determine the incidence of rejection and identify factors associated with the first episode of rejection in the first year after HTx. RESULTS: Data were reviewed in 1,852 patients from 36 centers. The incidence of rejection declined over 13 years at a rate of -2.58 +/- 0.41 (p < 0.001) from approximately 60% to 40% (p < 0.001). The mean number of episodes of rejection also significantly fell at a rate of -0.05 +/- 0.01 per patient/year from 1.19 to 0.66 (p < 0.001). The incidence of rejection with hemodynamic compromise and death from rejection did not change. Multivariate analysis for the risk of a first rejection episode demonstrated decreased risk of rejection with later year of HTx (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.85-0.91; p < 0.001) and use of mechanical support (OR, 0.65; 95% CI, 0.42-0.99; p = 0.046). Increased risk of rejection was associated with positive donor-specific crossmatch (OR, 1.85; 95% CI, 1.18-2.88; p = 0.007) and older recipient age (OR, 1.05; 95% CI, 1.02-1.07; p < 0.001). CONCLUSIONS: Although the overall incidence and prevalence of rejection has substantially decreased over time in pediatric HTx recipients in the first year after HTx, the rate of rejection with hemodynamic compromise or death from rejection remains unchanged.