In 11 patients with moderately severe multiple sclerosis, lasting 11.2 +/- 7.3 years, in stable condition, and in 10 age- and sex-matched control subjects, we investigated lung function, respiratory muscle strength, and ventilatory control system. Respiratory muscle strength was assessed by measuring maximal inspiratory and expiratory mouth pressures (Pimax and Pemax, respectively). Respiratory central drive was evaluated in terms of neuromuscular (P0.1) and ventilatory (Ve) output, breathing room air and during CO2 rebreathing. In the absence of any significant impairment of lung function, patients showed a reduction of Pimax and Pemax amounting to about 40 percent and 60 percent of the predicted value at functional residual capacity (FRC), respectively; a significant, inverse correlation was found between both Pimax and Pemax at FRC and the severity score of the disease. While at rest Ve was similar to that of control subjects, baseline P0.1 was significantly higher in patients (1.97 +/- 0.79 vs 0.97 +/- 0.20 cm H2O, p < 0.005). Compared with the control group, during CO2 rebreathing P0.1/PetCO2 slope, although less steep, was not dissimilar in patients (0.34 +/- 0.13 vs 0.46 +/- 0.19 cm H2O/mm Hg, NS); on the other hand, Ve/PetCO2 slope was much lower in the patient group (1.93 +/- 0.91 vs 3.27 +/- 1.11 L/min/mm Hg, p < 0.01) and was significantly related to the functional stage of disease and to Pimax and Pemax values at FRC. These results indicate that in patients with clinically stable, moderately severe multiple sclerosis, the respiratory muscle function is abnormal. Moreover, the inspiratory drive at rest is increased and the drive response to CO2 appears normal, while the ventilatory response to CO2 is significantly impaired. Respiratory muscle weakness (and/or lack of coordination) could explain, at least in part, the lower ventilatory response in these patients, whereas the mechanism of increased rate of the initial inspiratory force generation remains unclear.