The autoimmune response seen in insulin-dependent diabetes mellitus (IDDM) includes a humoral immune response against human insulin. Early insulin treatment has been used to prevent IDDM in the rodent models of IDDM, and a prevention trial is underway in humans. The metabolic effects of insulin may not be involved in this prevention since, in NOD mice, the use of metabolically inert human insulin B chain was effective. We wished to ascertain whether immunization of diabetes-prone BB/W rats with insulin B chain, A chain, or both could alter the incidence of diabetes. Immunizations began by 30 days of age and the rats were followed until 120 days of age. Only immunization with insulin B chain plus adjuvant was effective in reducing the rate of diabetes. All immunization frequencies were effective, but a significantly lower rate of diabetes was achieved with injections every week. All of the doses tested resulted in significantly lower rates of diabetes. These data confirm in the BB rat model that immunization with insulin B chain in the presence of adjuvant can reduce diabetes incidence. The absence of any metabolic effect of B chain and the requirement for adjuvant suggest that this effect is mediated via modulation of the autoimmune response.