In total, 116 children were investigated to determine whether the interleukin (IL)-10 polymorphism influences the age at primary Epstein-Barr virus (EBV) infection. The promoter of IL-10 is polymorphic, with 3 known single base substitutions (G/A at -1082, C/T at -819, and C/A at -592), which form 3 haplotypes: GCC, ACC, and ATA. This study found that carriage of the ATA haplotype protects against early EBV infection. The presence of the ATA haplotype was associated with EBV seronegativity (odds ratio, 2.6; 95% confidence interval, 1.04-6.7; P=.04), when controlled by age. To examine the effect of haplotypes on IL-10 production, IL-10 plasma levels were measured in 50 newborns and 400 adults and were correlated with the IL-10 haplotype. The IL-10 levels were significantly higher in the ATA carriers than in the noncarriers. These data suggest that the IL-10 ATA haplotype confers protection against primary EBV infection and that the effect is mediated by high IL-10 levels.