Large-scale randomized trials of positive airway pressure (PAP) efficacy have been largely negative yet PAP adherence was notably sub-optimal across the trials. To address this limitation, evidence-based PAP adherence protocols embedded within the larger trial protocol are recommended. The complexity of such protocols will be dependent on adequacy of resources, including funding and inclusion of behavioral scientist experts on the scientific team, and trial-specific considerations (e.g., target population) and methods. Recommendations for optimizing PAP adherence in large-scale trials are set forth that address rigor and reproducibility.