The role of chemical control instability in the pathogenesis of obstructive sleep apnea (OSA) is not clear. We studied 32 patients with OSA during sleep while their upper airway was stabilized with continuous positive airway pressure. Twelve patients had repetitive OSA whenever they were asleep, regardless of body position or sleep stage, and were classified as having severe OSA (apnea-hypopnea index [AHI] = 88 +/- 19). The remaining 20 patients had sporadic OSA or repetitive OSA for only part of the time (mild/moderate OSA; AHI = 27 +/- 16). Susceptibility to periodic breathing (PB) was assessed by gradually increasing controller gain, using proportional assist ventilation. The increase in loop gain (LG) at each assist level was quantified from the ratio of assisted tidal volume (VT) to the VT obtained during single-breath reloading tests (VT amplification factor [VTAF]). Nine of 12 patients with severe OSA developed PB, with recurrent central apneas, whereas only six of 20 patients in the mild/moderate group developed PB (p < 0.02). This difference was observed despite the subjection of the mild/moderate group to greater amplification of LG; the highest values of VTAF in the mild/moderate and severe groups were 2.7 +/- 1.0 and 1.9 +/- 0.7, respectively (p < 0.01). We conclude that the chemical control system is more unstable in patients with severe OSA than in patients with milder OSA. We speculate that this may contribute to the severity of OSA, at least in some patients.