To investigate the effects of the autonomic nervous system on control of breathing, the neuromuscular (mouth occlusion pressure at 0.1 s after onset of inspiration [P0.1]) and ventilatory (minute ventilation [VE]) response to progressive hyperoxic hypercapnia was assessed in diabetic patients with autonomic dysfunction of different severity. Eighteen diabetics with autonomic neuropathy, nine with parasympathetic damage (DANp), and nine with parasympathetic and sympathetic damage (DANp+s), as indicated by marked postural hypotension, low increment of diastolic BP during sustained handgrip, and lowest resting catecholamine plasma levels, were studied together with a group of 10 diabetic patients without autonomic neuropathy (D) and a group of 10 normal subjects (C). All subjects had pulmonary function tests, including maximal voluntary ventilation and diffusion of carbon monoxide, measurements of respiratory muscle strength as maximal inspiratory mouth pressure (MIP) and maximal expiratory mouth pressure (MEP), and a CO2 rebreathing test (Read's method). Although in the normal range, lung volumes and FEV1 and forced expiratory flows were lower in the DANp and DANp+s groups than in the D and C groups, MIP and MEP were similar among C and diabetic groups, as well as resting P0.1, VE, tidal volume (VT), and respiratory rate (RR). The slope of the linear relationship between P0.1 and end-tidal PCO2 (PETCO2) was higher in DANp+s (0.63±0.07 cm H2O/mm Hg) than in C (0.45±0.06 cm H2O/mm Hg; p<0.05) and three times greater in DANp+s than in D (0.26±0.03 cm H2O/mm Hg; p<0.001) and DANp (0.24±0.03 cm H2O/mm Hg; p<0.001), who in turn showed a lower ΔP0.1/ΔPETCO2 than C. The VE increase with increasing PETCO2 was greater in DANp+s (3.70±0.85 L/min/mm Hg) than in DANp (2.13±0.20 L/min/mm Hg; p<0.05) and D (2.37±0.40 L/min/mm Hg; p=0.07), but not significantly higher from that of C (3.17±0.36 L/min/mm Hg). No differences were found for ΔVT/ΔPETCO2 among the groups, whereas the ΔRR/ΔPETCO2 relationship was steeper in DANp+s than in DANp (p<0.05) and D (p=0.055). These data reflect a depressed CO2 response both in D and DANp. The presumable decrease of the sympathetic nerve traffic in DANp+s appears to reverse this abnormality. DANp+s, however, exhibit an enhanced CO2 neuromuscular response even in respect to C, suggesting that the sympathetic nervous system might modulate the output of the respiratory centers to hypercapnic stimulus.