Nonobese diabetic (NOD) mice develop spontaneous insulin‐dependent diabetes mellitus (IDDM), and the pancreas‐infiltrating T cells invariably show a Th1 phenotype. We demonstrated here that the interleukin (IL)‐12 antagonist (p40)₂ can deviate the default Th1 development of naive T cell receptor (TCR)‐transgenic CD4⁺ cells to the Th2 pathway in vitro. Although (p40)₂ does not modify the cytokine profile of polarized Th1 cells, it prevents further recruitment of CD4⁺ cells into the Th1 subset. To study the involvement of Th1 and Th2 cells in the initiation and progression of IDDM, we targeted endogenous IL‐12 by administration of (p40)₂ in NOD mice. (p40)₂ administration to NOD mice inhibits interferon‐γ but not IL‐10 production in response to lipopolysaccharide (LPS) or to the putative autoantigen IA‐2. Serum immunoglobulin isotypes determined after (p40)₂ treatment indicate an increase in Th2 and a decrease in Th1 helper activity. Administration of (p40)₂ from 3 weeks of age onwards, before the onset of insulitis, results in the deviation of pancreas‐infiltrating CD4⁺ but not CD8⁺ cells to the Th2 phenotype as well as in the reduction of spontaneous and cyclophosphamide‐accelerated IDDM. After treating NOD mice with (p40)₂ from 9 weeks of age, when insulitis is well established, few Th2 and a reduced percentage of Th1 cells are found in the pancreas. This is associated with a slightly decreased incidence of spontaneous IDDM, but no protection from cyclophosphamide‐accelerated IDDM. In conclusion, deviation of pancreas‐infiltrating CD4⁺ cells to Th2 is associated with protection from IDDM. However, targeting IL‐12 after the onset of insulitis, when the pancreas contains polarized Th1 cells, is not sufficient to induce an effective immune deviation able to significantly modify the course of disease.