Identical twins of young adult Hodgkin lymphoma case subjects are much more likely to develop the disease compared with fraternal twins of case subjects, suggesting a genetic determinant. Interleukin 6 (IL-6) levels are increased in patients with Hodgkin lymphoma and are correlated with a poor prognosis. We hypothesized that a heritable abnormality in IL-6 regulation may predispose to young adult Hodgkin lymphoma. We obtained blood specimens from 88 young adult Hodgkin lymphoma case subjects and their twins as well as from 87 matched control subjects. IL-6 was measured from unstimulated peripheral blood mononuclear cell (PBMC) supernatant with enzyme-linked immunosorbent assays (ELISAs) and compared by using analysis of covariance. Unaffected identical twins of case subjects (surrogate case subjects) had a 87.8% higher IL-6 level compared with matched control subjects (mean difference, +483.7 pg/mL, P =.04). Analysis of the IL-6 174G>C promoter polymorphism genotypes showed that risk decreased with an increasing number of C alleles (P =.01). The CC (low secreting) genotype was associated with a decreased risk of young adult Hodgkin lymphoma relative to the GG (high secreting) genotype (odds ratio [OR] =.29; P =.03). Risk was decreased for both nodular sclerosis and other subtypes. Persons with genetically determined lower IL-6 levels may be less susceptible to young adult Hodgkin lymphoma.