Study objectives: We sought to determine whether breathing heliox or using nasal noninvasive positive pressure ventilation (NIPPV) would produce immediate improvements in exercise capability in patients with COPD, and whether training for 6 weeks with one of these modalities would result in greater exercise improvement than with training unassisted. Setting: US military medical center. Methods: Thirty-nine patients with severe COPD (mean FEV1 of 33.5% predicted) underwent three incremental treadmill tests to exhaustion unassisted, breathing heliox, or breathing with NIPPV. They were then randomized to undergo 6 weeks of twice-weekly rehabilitation with unassisted exercise training (UT group), training while breathing heliox (HT group), or training while breathing with NIPPV (NT group). The three exercise tests were then repeated. Results: Heliox treatment did not produce any immediate benefit in exercise time or maximum workload in the 39 patients initially tested, the 32 patients who completed the protocol, or the HT group. Furthermore, no training advantage was evident in the HT group (n = 10) compared to the UT group (n = 11). NIPPV did not produce an immediate benefit in the initial tests, but produced a small increase in exercise time in the 32 patients completing the protocol in the final tests. This effect was primarily because of the NT group, who exercised significantly longer (mean ± SD, 16.8 ± 4.9 min vs 14.2 ± 5.6 min, p = 0.0045) and to a higher workload (4.46 ± 1.55 metabolic equivalents [METs] vs 4.09 ± 1.75 METs, respectively; p = 0.038) when tested using the ventilator. Compared to the UT group, the NT group started out with a lower exercise time (7.9 ± 3.5 min vs 12.3 ± 5.2 min, p = 0.031) in preliminary testing, but the statistical difference was eliminated in the final tests (14.2 ± 5.6 min vs 16.0 ± 5.8 min, respectively; p = 0.451). The NT group actually slightly exceeded the UT group when they used the ventilator in final testing, although this was not statistically significant (16.8 ± 4.9 min vs 16.0 ± 5.8 min, respectively). Conclusion: Heliox treatment does not appear to offer an immediate or training advantage with exercise in patients with COPD. For patients who have undergone regular exercise conditioning with NIPPV, use of the ventilator produces an immediate improvement in both exercise time and maximum workload attained, and it may confer a training advantage.