In view of the reported association of insulin-dependent diabetes mellitus (IDDM) with viral infections, (non-) islet-specific immune changes, and partial immunodeficiencies, we used immunonephelometry to measure circulating levels of IgM, IgG, and IgA in a registry-based group of IDDM patients under age 40 years at clinical onset (n= 397) and in age-matched nondiabetic siblings (n= 316) and control subjects (n= 322). Overall, IgM and IgA concentrations were higher, and IgG concentrations lower, in patients than in control subjects or siblings (P<0.001). In siblings, IgM concentrations were higher than in control subjects (P<0.001). Using age-adjusted reference intervals, abnormal Ig concentrations were noted in 27% of the patients at onset versus only 10% of the siblings and 7% of the control subjects (P<0.001). For onset between 20 and 40 years (n= 220), 30% of the patients presented either increased IgM levels (21 %) or decreased IgG levels (11 %). Both independent phenomena occurred regardless of diabetes-associated immune and genetic markers. In patients and siblings, IgM levels were positively correlated with pancreatic lipase activity. In diabetic children (0–9 years;n= 65), a subgroup presented increased IgA levels (15%) in association with the highest HLA DQ-linked genetic risk and elevated IgM levels. The changes in total Ig concentrations at onset were largely reversed under insulin therapy. They may reflect exposure to environmental triggers, such as viral infections, or to (relative) insulinopenia prior to clinical disease onset. Whatever their cause, different serum Ig levels exist in different age groups of recent-onset IDDM patients.