To investigate the activity of the endogenous opioid system in patients with insulin-dependent diabetes mellitus during ventilatory stress situations, we measured plasma β-endorphin levels in six male and five female diabetic patients breathing against fatiguing inspiratory resistive loads. The patients had to generate with each inspiration an esophageal pressure (Pes) 80% of maximum until they were exhausted and could no longer develop target Pes. The loaded breathing run was repeated three times with a 1-min interval between each run. Duty cycle, tidal volume, and breathing frequency were constant in all tasks. For each run plasma β-endorphin levels were measured, inspiratory effort sensation assessed using a modified Borg scale, and inspiratory muscle endurance evaluated by the length of time the task could be maintained (Tlim). A group of 11 sex-, age-, height-, and weight-matched healthy individuals served as control subjects. Tlim was significantly lower in the diabetic patients. Evaluating respiratory effort during the three test runs in control subjects at a time corresponding to the break point of loaded breathing in patients showed significantly lower Borg ratings in the control group than in the patient group. Baseline plasma β-endorphin was significantly lower in the diabetic patients (10.6 ± 2.1 versus 27.0 ± 4.2 pg/ml, p < 0.01). Additionally, whereas resistive loaded breathing caused a further increase in plasma β-endorphin concentration in the control group (p < 0.005), absolutely no increase was found in the diabetic patients. We conclude that the endogenous opioid system in insulin-dependent diabetic patients does not respond to stress caused by breathing against fatiguing inspiratory resistive loads.