INTRODUCTION: Obesity hypoventilation syndrome (OHS) is a major respiratory complication caused by severe obesity, being associated with significant morbidity, negative impacts on quality of life and reduced survival if not treated appropriately. Positive airway pressure therapy is the first-line treatment for OHS although the optimal modality remains unclear. The goal of this study is to identify the efficacy of home bilevel positive airway pressure therapy by comparison to continuous positive airway pressure therapy and determine the best strategy for patients with OHS. METHODS AND ANALYSIS: This study will be conducted following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement. We will search the following databases: PubMed, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL. Ongoing studies will be identified through the ClinicalTrials.gov and WHO International Clinical Trials Registry Platform Search Portal. Grey literature will be recognised through Google Scholar and other search engines. Only randomised controlled trials meeting the eligibility criteria will be included. The risk of bias of the included studies will be evaluated through the Cochrane Collaboration's tool. RevMan V.5.3.5 software will be used for data analysis. The Q statistic and I index will be used for investigating heterogeneity, and subgroup analysis or sensitivity analysis will be used to explore the source of heterogeneity. In addition, the Grading of Recommendations Assessment, Development and Evaluation system will be used to inspect the quality of evidence. ETHICS AND DISSEMINATION: Ethics approval is not required because this study contains no primary data collected from humans. This systematic review and meta-analysis will be submitted to a peer-reviewed journal for publication. PROSPERO REGISTRATION NUMBER: CRD42017078369.