Numerous studies have suggested that stress precipitates type I diabetes. Because stress-elicited hyperglycemia may play a role in this effect, we measured the influence of acute immobilization (90 min) upon plasma glucose and insulin levels in nonobese diabetic (NOD) mice, a spontaneous model of type I diabetes. To this end, prediabetic 8-week-old mice of both sexes were compared to age- and sex-matched C57BL/6 control mice. Baseline plasma glucose levels and immobilization-elicited hyperglycemia were both lower in male and female NOD mice compared to their C57BL/6 counterparts. However, the maximal effects of immobilization upon plasma insulin (and corticosterone) levels were not different between NOD and C57BL/6 mice. When subjected to a metabolic stressor, such as 2-deoxyglucose-induced neuroglucopenia, both strains responded with similar increases in plasma glucose levels. This change was associated with hyperinsulinemia, whose amplitude was lower in NOD than in C57BL/6 females. Lastly, administration of the alpha 2-adrenergic agonist, clonidine, elicited a marked increase in plasma glucose levels, whose amplitude was independent of the strain. The results from this study indicate that the two strains differed in their glycemic response to a psychological, but not to a metabolic, stressor. Because NOD mice were found to exhibit increased locomotion when placed for the first time in an open field, it is suggested that behavioral differences contribute to this differential effect of immobilization upon circulating glucose levels in NOD and C57BL/6 mice.