In normal subjects 2 min of maximal voluntary hyperventilation results in failure of tension generation and low-frequency fatigue of the diaphragm. Patients with severe chronic obstructive pulmonary disease (COPD) do not develop diaphragm fatigue during exhaustive treadmill exercise despite excessive inspiratory muscle loading and we hypothesized that they might be relatively resistant to the development of diaphragm fatigue during maximal ventilation. In six patients with severe COPD (mean FEV1 0.671) we therefore loaded the diaphragm using 2 min of maximal isocapnic ventilation (MIV). Initial mean ventilation was 28.6 L/min and diaphragm pressure-time product (PTPdi) 602 cm H2O x s/min; these values were sustained throughout MIV without significant decline. Mean twitch transdiaphragmatic pressure (Tw Pdi) was 19.7 cm H2O 25 min after a control run and 20.5 cm H2O at the same time after MIV [corrected]. Compared with normal subjects previously studied in our laboratory (Hamnegard, C.-H., et al. Eur. Respir. J. 1996;9:241-247) the reduction in PTPdi was disproportionately greater than the reduction in Tw Pdi. We conclude that, unlike normal subjects, 2 min of MIV causes neither failure of diaphragm performance nor low-frequency diaphragm fatigue in patients with severe COPD. It is likely that the diaphragm makes a relatively limited contribution to the generation of maximal levels of ventilation in severe COPD.