Environmental factors appear to be nongenetic risks of importance in the progression of insulin-dependent diabetes mellitus (IDDM) or type 1 diabetes, whose mechanisms are not yet well understood. Stressful life events, in particular, have been linked to the expression of overt diabetes in humans. However, in rodent models of IDDM, contradictory data exist concerning the effects of stress on the disease. Here, we show that a stressor, such as long-term repeated injections of vehicle (0.9% saline), was able to delay the appearance and/or decrease the incidence of diabetes in both sexes of NOD mice. Short-term chronic stress applied from the 6th to the 8th week of age by a combination of multiple stressors (overcrowding + immobilization + cold exposure + anesthesia) protected NOD mice from diabetes, particularly males. In contrast, prenatal stress, induced by immobilization of the mothers during the third part of pregnancy, accelerated the onset and increased the prevalence of diabetes at 30 weeks of age in NOD females, while it had no effect in males. Finally, adrenalectomy appears to aggravate the development of diabetes in NOD mice, particularly in males. In conclusion, these data demonstrate that the appearance of diabetes in NOD mice is extremely sensitive to various experimental and environmental conditions. These results are discussed in the context of the complex neuroendocrine-immune interactions which occur during the progression of IDDM, with a particular focus on glucocorticoids and cytokines.