Patients with complex sleep apnea syndrome (CompSAS) have obstructive sleep apnea but develop troublesome central sleep apnea activity or Cheyne-Stokes breathing when provided continuous positive airway pressure (CPAP) therapy. We examined whether CompSAS activity persists with long-term CPAP treatment. We retrospectively identified all patients with CompSAS who underwent two therapeutic polysomnograms (PSGs) separated by at least 1 month during 2003-2005. We compared PSG findings between the initial and follow-up study and noted clinical responses to therapy. We identified 13 CompSAS patients meeting criteria. Most follow-up PSGs were ordered after an abnormal overnight oximetry on CPAP or because of CPAP intolerance after 195 (49-562) days. The residual apnea-hypopnea index (AHI) on CPAP decreased from 26 (23-40) on the first PSG to 7 (3-21.5) on the follow-up PSG. Only seven patients reached AHI < 10 and 6 had AHI > or = 10 ("CPAP nonresponders") at follow-up. "CPAP nonresponders" were sleepier (Epworth Sleepiness Score 13 [12.5-14] vs 9 [6-9.5], p = 0.03) and trended toward lower body mass index (29.7 [28.6-31.6] vs 34.3 [32.5-35.1], p = 0.06). Both groups were equally compliant with CPAP therapy. Although the AHI tends to improve over time in CompSAS patients treated with CPAP, in this retrospective study nearly half-maintained a persistently elevated AHI. A prospective trial is merited to determine the optimal treatment for these patients.