Objectives: To determine factors that are associated with OSA therapy outcomes with auto-titrating positive airway pressure (APAP).Methods: We sequentially grouped patients from a retrospective cohort based on APAP efficacy (sufficiently vs. insufficiently treated; insufficiently treatment defined as residual AHI of ≥ 5), therapy adherence (adherent vs. non-adherent, non-adherence defined as < 70% usage for ≥ 4 h/night), and therapy outcomes (optimal vs. non-optimal and non-optimal outcomes defined as non-adherent and/or insufficiently treated). We subsequently compared each group.Results: The insufficiently treated were older (68.4 ± 12.5 vs. 60.4 ± 13.1 years, p < 0.01) and had lower BMI (31.9 ± 6.3 vs. 37.9 ± 9.1 kg/m2, p < 0.01). They had higher baseline central apnea indices (CAI), longer leaks, higher peak pressures, and were less compliant. The non-adherent were younger (61.1 ± 12.6 vs. 65.5 ± 13.2 years, p = 0.03) and comprised more females (56.1 vs. 43.9%, p = 0.04). The leak duration per usage hour was higher in the non-compliant (median: 1.5; IQR 7.9 vs. median: 0.3; IQR 1.9 min/h; p < 0.01). The non-optimally treated had lower BMI, longer leaks, and less nightly usage. Multivariate analyses showed that leak duration was the common factor associated with treatment effectiveness and optimal therapy outcomes.Conclusions: Various demographic and clinical factors were associated with treatment efficacy and adherence. However, leak duration was the common factor related to treatment efficacy and overall optimal therapy outcomes.