Increased use of serial EBV-PCR monitoring after pediatric transplantation has led to the identification of asymptomatic patients who carry very high viral loads over prolonged periods. The significance of this high-load state is unknown. We speculated that this state may identify patients at high risk for development of late PTLD/lymphoma. We reviewed data on 71 pediatric heart recipients who had serial viral load monitoring since 1997. Chronic high-load state was defined as the presence of >16,000 genome copies/mL whole blood on > or =50% of samples over at least 6 months. Among 20 high-load carriers (eight following prior PTLD, seven with prior symptomatic EBV infection, five without previous EBV disease), 9 (45%) developed late-onset PTLD 2.5-8.4 years posttransplant (including with four Burkitt's lymphoma). Among 51 controls with low (n = 39) or absent (n = 12) loads, only 2 (4%; p < 0.001 absent/low vs. high load) developed late PTLD/lymphoma. By multivariable analysis, high-load carrier state (OR = 12.4, 95% CI 2.1-74.4) and prior history of PTLD (OR = 10.7, 95% CI 1.9-60.6) independently predicted late PTLD. A chronic high EBV-load state is not benign and is a predictor of de novo or recurrent PTLD.