OBJECTIVE.: The objective of this study was to determine the association between the genetic polymorphisms of proinflammatory and regulatory cytokines and long-term rates of repeat and late acute rejection episodes in pediatric heart transplant (PHTx) recipients. METHODS.: Three hundred twenty-three PHTx recipients: 205 White non-Hispanic, 43 Black non-Hispanic, and 75 Hispanic were analyzed for time to first repeat and late acute rejection episodes by race, age at transplantation, and gene polymorphism (interleukin [IL]-6, -174 G/C, IL-10, -1082 G/A, -819 C/T, 592 C/A; vascular endothelial growth factor (VEGF) -2578 C/A, -460 C/T, +405 C/G; tumor necrosis factor alpha (TNF-α)-308 G/A). RESULTS.: Recipient black race and older age at transplant were risk factors for both repeat and late rejections, though black race was more significantly related to late rejection (P=0.006). Individually, TNF-α high, IL-6 high, VEGF high, and IL-10 low phenotypes did not impact the risk of repeat or late rejection. However, the combination VEGF high/IL-6 high and IL-10 low was associated with increased estimated risk of late rejection (P=0.0004) and only marginally with repeat rejection (P=0.051). In a multivariate analysis, adjusting for age and race, VEGF high/IL-6 high and IL-10 low still remained an independent risk factor for late acute rejection (RR=1.91, P<0.001). CONCLUSION.: This is the largest multicenter study to document the impact of genetic polymorphism combinations on PHTx recipients' outcome. The high proinflammatory (VEGF high/IL-6 high) and lower regulatory (IL-10 low) cytokine gene polymorphism profile exhibited increased risk for late rejection, irrespective of age and race/ethnicity. © 2008 by Lippincott Williams & Wilkins.