Some patients with the sleep apnea/hypopnea syndrome (SAHS) remain subjectively and objectively sleepy despite using effective continuous positive airway pressure (CPAP) therapy. The aim of this single center study was to determine the efficacy and safety of the novel wake-promoting medication modafinil in the treatment of CPAP-resistant daytime sleepiness. Thirty sleep apneics receiving effective CPAP therapy (objective use, 6.5 +/- 1.1 h/night) received daily single doses of 400 mg modafinil or placebo for 2 wk in a double-blind randomized crossover design. Outcome measures were assessed at baseline and at the end of both 2-wk treatment periods. Treatment periods were separated by a 1-wk washout. Modafinil had no effect on sleepiness as measured by the Epworth Sleepiness Scale or the Multiple Sleep Latency Test (p > 0.1); however, significant improvements in alertness were found with the Maintenance of Wakefulness Test (modafinil 18.3 +/- 3.9 min; placebo, 16.6 +/- 5.0 min; p < 0.02). No significant treatment-related improvements in cognitive performance or quality of life were found with modafinil (all p > 0.05). There was a significant reduction in CPAP use on modafinil compared to placebo (6.3 +/- 1 h/ night; 6.5 +/- 1, p = 0.03). This study suggests that modafinil may improve some aspects of alertness in patients with SAHS who remain sleepy during CPAP therapy, but further studies are required to assess the significance of the reduction in CPAP use.