From July 1984 through June 1987, we sought referral of all newly diagnosed cases of insulin-dependent diabetes mellitus aged 0-29 years in a 14-county area of southern Wisconsin. Each case was asked to identify an age- and sex-matched friend control. Blood specimens were obtained for group B Coxsackievirus immunoglobulin M (IgM) neutralizing antibody titer on cases and controls and HLA-DR typing of cases. There were 225 cases referred, of whom 194 participated. Of these, 134 had both HLA-DR typing and an initial serum specimen drawn within 59 days of diagnosis. Only two of 50 insulin-dependent diabetes mellitus cases less than age 9 years had positive (greater than or equal to 1:16) group B Coxsackievirus IgM titers. Fifteen of 84 cases aged 10-29 years (17.8%) were group B Coxsackievirus IgM positive, compared with five of 71 controls (7.0%). However, group B Coxsackievirus IgM antibody positivity was concentrated in HLA-DR3-positive cases (10 of 39, odds ratio = 4.55, 95% confidence interval 1.26-18.27, p less than 0.01). HLA-DR3-negative cases were not different from controls in group B Coxsackievirus IgM prevalence. Eighty-three percent of the cases and 86% of the group B Coxsackievirus IgM-positive cases were referred in the first 24 months of study. These data demonstrate an association between group B Coxsackievirus infections and onset of insulin-dependent diabetes mellitus only in HLA-DR3-positive persons aged 10 years or older. The data also suggest that diabetogenic group B Coxsackievirus strains may circulate only periodically; however, a longer period of study is needed to examine this possibility.