Abstract: We sought to assess the augmentation of brief behavioral therapy for insomnia (BBTI) with eszopiclone (ESZ) over BBTI alone for the treatment of chronic insomnia on sleep quality, sleep indices, and continuous positive airway pressure (CPAP) adherence in PTSD veterans with COMISA. The pilot trial involved 53 PTSD patients (46 males and 7 females, mean age 48.2±8.3 years) with COMISA randomized to combination therapy of BBTI plus 2 weeks of eszopiclone (2 mg/d) or BBTI alone with follow-up visits conducted at 6 and 24 weeks. The main outcome measure was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI). A significant decrease in PSQI scores was observed between baseline and 24 weeks for BBTI plus ESZ (-5.24 [95% CI, -6.55 to -3.94]; p < 0.001) and BBTI-only (-5.45 [95%CI, -6.75 to -4.14]; p < 0.001). No significant group allocation effects x time interactions were detected. Similar improvements were recorded for ISI between baseline and 24 weeks (BBTI plus ESZ (-8.32 [95%CI, -10.51 to -6.14]; p < 0.001) and BBTI-only (-8.64 [95%CI, -10.88 to -6.41]; p < 0.001)) with no interaction effect between treatment groups x time. Combination therapy produced a higher remission rate of insomnia at 6 weeks, with both interventions achieving comparable rates at 24 weeks. Results of the mixed effect models for CPAP use revealed no group x time interaction effects. In patients with COMISA, the combination of eszopiclone with BBTI resulted in comparable improvement in sleep quality of life to that achieved with BBTI-only therapy. Although the addition of eszopiclone to BBTI conferred an early benefit in remission rate of insomnia relative to BBTI, both modalities achieved similar outcomes at long-term follow-up. Clinical Trial Registration This study was registered with ClinicalTrials.gov (Identifier NCT03937713).