Application of continuous positive airway pressure (CPAP) as the standard treatment for sleep apnea/hypopnea syndrome (SAHS) is a moot point. Studies on the effectiveness of this treatment have been challenged because of the lack of a suitable placebo. The recent description of a true placebo (sham CPAP) prompted us to conduct a randomized trial of CPAP or placebo to assess the effectiveness of CPAP in improving SAHS-related symptoms and daytime function in patients with moderate to severe SAHS. Forty-eight patients, stratified in four groups according to severity, were randomly allocated into two treatment groups (optimal and sham CPAP) for a 6-wk period. Of these, 45 completed follow-up (91% males; age: 54 +/- 10 yr; body mass index [BMI]: 32 +/- 6 kg/m(2); apnea-hypopnea index [AHI]: 54 +/- 19 events/h; and Epworth Sleepiness Scale [ESS]: 16 +/- 5). The ESS, a questionnaire on SAHS-related symptoms, Functional Outcomes Sleep Questionnaire (FOSQ), and the Short Form Health Survey (SF-36) were completed at inclusion and after treatment. After 10 d of washout, the placebo group was treated with optimal CPAP and reassessed before and after optimal CPAP. The group receiving optimal CPAP when compared with the group with sham CPAP showed considerably greater improvement in the relief of sleepiness (-9.5 versus -2.3, p < 0.001), other SAHS-related symptoms (-18.5 versus -4.5, p < 0.001), vigilance (+8.5 versus +3.4, p = 0.009), and general productivity (+4.0 versus +0.5, p = 0.04) FOSQ scales. Both groups used a similar number of hours for the optimal and the sham CPAP (4.3 versus 4.5, (p = NS). The patients initially treated with placebo CPAP improved significantly more when optimal CPAP was applied for ESS (-2.3 versus -6.7, p < 0.001) and other sleep apnea syndrome (SAS)-related symptoms (-4.5 versus -11.2, p = 0.02). Our study provides strong evidence of the effectiveness of CPAP treatment in improving symptoms and perceived health status in moderate to severe SAHS.