Polyinosinic polycytidilic acid (poly I:C), an inducer of α-interferon, accelerates the development of diabetes in diabetes-prone (DP) BioBreeding (BB) rats. This study investigates the effect of administering poly I:C to a diabetes-resistant (DR) strain of BB rats. We compared the incidence of diabetes, the degree of insulitis, the number of NK cells, helper-inducer cells, cytotoxic-suppressor cells, Ia⁺ T cells, RT6.1⁺ T cells, and NK cell bioactivity in DR rats treated with saline and with a 5 micrograms/g body wt (poly-5) dose and a 10 micrograms/g body wt (poly-10) dose of poly I:C. The incidence of diabetes was also compared with that of DP rats receiving poly-5. We found that both doses of poly I:C significantly induce the development of diabetes in the DR BB rat. However, treatment of DR rats with the higher dose induces a greater rate of development of diabetes and earlier onset of diabetes than the lower poly-5 dose. The rate of diabetes development and the mean age of onset were similar in poly-10–treated DR and poly-5–treated DP rats. A significant degree of insulitis occurred in all the poly I:C–treated DR rats, even those not developing diabetes. Peripheral blood NK cell number was greater in poly I:C than in saline-treated rats, after 2 wk of treatment and when killed. The percentage of OX19⁺ peripheral blood mononuclear cells expressing RT6.1 allotype or Ia antigen were similar in poly I:C– and saline-treated rats. of diabetes in poly-10–treated DR rats and poly-5–treated DP rats is consistent with a similar mechanism of poly I:C action in the DR and DP BB rats. Although the specific mechanism is not defined, NK cell numbers are elevated with poly I:C treatment. Alterations in RT6.1⁺ and la⁺ T cells do not appear to play a role.