The mortality of diabetic patients with autonomic neuropathy (DAN) is higher than that in those without autonomic neuropathy (DM). To test the hypothesis that this may be due to respiratory rather than cardiac dysfunction, we evaluated ventilatory responses to isocapnic-hypoxic and hyperoxic-hypercapnic conditions in 14 diabetic patients (8 DAN and 6 DM) and compared the results with those in 8 normal subjects. In all groups tested there was a significant linear correlation between end-tidal CO2 and minute ventilation and between end-tidal CO2 and mouth occlusion pressure (p100), as an index of the drive to breathe. There were no significant differences between the slopes and intercepts in the groups tested. A significant linear correlation was found between the O2 saturation and both minute ventilation and p100. There were no significant differences in the relationship between minute ventilation and O2 saturation, but the slopes and the intercepts of the regression lines of p100 vs. O2 saturation were significantly different in the DAN compared with those in normal subjects and DM. Additionally, five of eight patients with DAN lost their ventilatory drive and ventilatory responses to hypoxemia compared with only one of six DM. These findings suggest that a disorder in the ventilatory response to hypoxemia exists in some DAN.