Background. Cytokine polymorphisms may modulate immunologic reactivity, including graft-versus-host disease (GVHD). A single nucleotide polymorphism resulting in a thymine-to-guanine transition in the interleukin (IL)-2 gene promoter region occurs at position-330. In vitro studies have shown that the G allele is associated with early and sustained enhancement of IL-2 production, a so-called high-producer genotype. Because IL-2 is a proinflammatory cytokine, we hypothesized that recipients with high-producer genotypes would have increased frequency of GVHD after allogeneic bone marrow transplantation (BMT). Methods. We studied 95 consecutive donor and recipient pairs who received an unrelated donor BMT at the University of Minnesota. The median age at time of BMT was 14.1 years (range 0.9-54.8 years). Stem cells were human leukocyte antigen-A, B, and DRB1 matched in 70 cases (74%) and single-antigen mismatched in 25 cases (26%). GVHD prophylaxis consisted of cyclosporine-containing regimens (53%), T-cell depletion by elutriation (42%), and others (2%). Results. The probability of grade II-IV acute GVHD at day 100 was 36% (95% confidence interval 26%-46%) and was significantly affected by the presence of recipient IL-2 G allele. The probability of acute GVHD was 49% in 49 patients (52%) with at least one G allele compared with 24% in 42 patients (44%) with no G allele (P<0.01). In the Cox regression analysis, the presence of at least one IL-2 G allele was associated with a twofold increased risk of acute GVHD. Conclusions. If confirmed by others, our results indicate that more intensive GVHD prophylaxis is needed for patients with at least one IL-2 G allele, possibly directed toward blunting early host cell production of IL-2.