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STUDY OBJECTIVES: Hypoventilation associated with sleep-disordered breathing in inpatients is associated with higher risk of morbidity, hospitalizations, and death. In-hospital titration polysomnography qualifies patients for positive airway pressure (PAP) therapy and optimizes settings, but impact is unknown. This study describes a process for in-hospital sleep testing and evaluates subsequent PAP adherence and readmission. METHODS: A retrospective cohort of patients with hypoventilation and in-hospital titration polysomnography with available PAP data were analyzed to determine whether PAP adherence was associated with 90-day readmission. Absolute differences were obtained using logistic regression models. Models were adjusted for body mass index, age, and Elixhauser index. PAP adherence and nonadherence were defined as ≥ 4 and < 4 hours of daily average use prior to readmission or first 90 days postdischarge. RESULTS: Eighty-one patients, 50.6% male, with age (mean ± SD) 61.1 ± 13.5 years were included. Comorbid sleep disorders included 91.4% with obstructive sleep apnea and 23.5% with central sleep apnea. Twenty-eight of 52 (53.8%) nonadherent and 6 of 29 (20.7%) adherent patients had 90-day readmissions. Eleven (13.6%) patients (all nonadherent) were readmitted within 2 weeks of discharge. The adjusted model showed a 35.6% (95% confidence interval 15.9–55.2%) reduction in 90-day readmission in the adherent group compared with the nonadherent group (P = .004). Similar reductions in readmission were found with adherence of ≥ 50% and ≥ 70% of days ≥ 4 hours. Male sex, treatment with iVAPS (intelligent volume-assured pressure support), and highest CO(2) ≥ 60 mmHg on polysomnography were associated with the largest differences in readmission rates between adherent and nonadherent patients. CONCLUSIONS: Adherence to optimized PAP therapy after in-hospital titration polysomnography in patients with hypoventilation may decrease readmissions. CITATION: Johnson KG, Rastegar V, Scuderi N, Johnson DC, Visintainer P. PAP therapy and readmission rates after in-hospital laboratory titration polysomnography in patients with hypoventilation. J Clin Sleep Med. 2022;18(7):1739–1748.