Persons with acquired immunodeficiency syndrome (AIDS) have increased risk for non-Hodgkin's lymphoma (NHL). Recent studies have reported the detection of DNA sequences from simian virus 40 (SV40), a macaque polyomavirus that contaminated early poliovirus vaccines, in a large proportion of AIDS-associated NHLs. To examine the association between SV40 exposure and NHL risk, we analyzed data from a U.S. registry-based cohort study of persons with AIDS (1980-96). We calculated NHL incidence in persons born in 1958-61 (exposed to SV40-contaminated poliovirus vaccine as children, n = 39,468) and in 1964-67 (born after vaccines were cleared of SV40 and thus unexposed, n = 17,340). Among persons with AIDS, NHL incidence was 11.7 per 1,000 person-years in SV40-exposed individuals (616 NHL cases) and 10.1 per 1,000 person-years in SV40-unexposed individuals (230 cases; unadjusted relative risk 1.15, 95% CI 0.99-1.34, p = 0.06). Because of differences in cohorts' birth years and the evolving demographics of the AIDS epidemic, SV40-exposed subjects were older at AIDS onset than unexposed subjects (mean age 32.0 vs. 27.2 years, p < 0.0001), and the cohorts differed by sex (p < 0.0001) and ethnic group (p < 0.0001). Since NHL incidence was relatively high among whites (p < 0.0001) and homosexual males (p < 0.0001) and increased with age (p = 0.09), comparisons required adjustments for these factors. After adjustment, SV40 exposure was not associated with NHL incidence (adjusted relative risk 0.97, 95% CI 0.79-1.20, p = 0.80). We conclude that childhood exposure to SV40 through receipt of contaminated poliovirus vaccine was not associated with increased risk for AIDS-associated NHL. Our findings do not support a role for SV40 in lymphomagenesis among immunosuppressed persons.