Young adult Hodgkin lymphoma (YAHL) is associated clinically with altered immunity, including a systemic defect in cell-mediated responses. There is strong evidence of a genetic contribution to risk, so we hypothesized that heritable alterations in cytokine production associated with Th1 function may contribute to susceptibility. We identified twin pairs in whom at least one member had YAHL and measured interleukin-2 (IL-2), interleukin-12 (IL-12), and interferon-gamma (IFN-gamma) levels in PHA-stimulated peripheral blood mononuclear cell supernatant in 90 case-twins, 84 of their disease-free twins (unaffected cotwins), and 90 matched controls. Mean difference and mean percentage difference in cytokine levels between case-twins and controls, and unaffected cotwins and controls were determined using analysis of covariance. YAHL case-twins and their unaffected cotwins had IL-12 levels that were 60.6% (P=.002) and 49% (P=.04) lower than those of their matched controls, respectively. IL-2 levels were significantly higher in case-twins (P=.049), but not unaffected cotwins (P=.57), compared with controls. Differences in IFN-gamma levels were not statistically significant in either comparison. An IL-12 polymorphism known to regulate expression was associated with a 2.8-fold (P=.03) increase in YAHL risk. Thus, both case-twins and their unaffected cotwins had a decreased ability to produce IL-12, which may contribute to YAHL susceptibility.