Background: The initial experience with continuous positive airway pressure (CPAP) may predict subsequent compliance. In a retrospective study, we found that premedication with nonbenzodiazepine sedative-hypnotic agents during CPAP titration polysomnography independently predicted short-term compliance. To validate these findings, we conducted a prospective clinical trial to assess whether premedication with eszopiclone prior to CPAP titration would improve short-term CPAP compliance. Methods: Subjects in this randomized, double-blind, placebo-controlled trial received 3 mg of eszopiclone or matching placebo prior to undergoing CPAP titration polysomnography. We compared the quality of CPAP titrations and objective measures of compliance during the first 4 to 6 weeks of therapy between the two groups. Results: We enrolled 117 subjects, and 98 subjects completed the protocol (eszopiclone, 50 subjects; placebo, 48 subjects). Other than there being more women in the eszopiclone group, the groups were similar at baseline. Compared with placebo, premedication with eszopiclone significantly improved mean (± SD) sleep efficiency (87.8 5.8% vs 80.1 ± 10.5%, respectively; p = 0.002) and mean total sleep time (350.9 ± 33.6 min vs 319.7 ± 48.7 min, respectively; p = 0.007). A trend toward improved sleep latency (19.4 ± 16.1 min vs 31.8 ± 30.4 min, respectively; p = 0.08) and the number of residual obstructive events observed at the final CPAP pressure (6.4 ±7 events/h vs 12.8 ± 14.6 events/h, respectively; p = 0.08) during polysomnography was found. Eszopiclone significantly improved CPAP compliance. Among subjects premedicated with eszopiclone, CPAP was used on a higher percentage of nights (75.9 ± 20.0% vs 60.1 ± 24.3%, respectively; p = 0.005) and for more hours per night (4.8 ± 1.5 h vs 3.9 ± 1.8 h, respectively; p = 0.03). Conclusions: Premedication with eszopiclone on the night of CPAP titration improved the quality of CPAP titration and led to significantly greater short-term compliance. Trial registration: ClinicalTrials.gov Identifier: NCT00507117.