The intrinsic nature of opioids to suppress respiratory function is of particular concern among patients with obstructive sleep apnea (OSA). The association of OSA with increased perioperative risk has raised the question of whether patients with OSA are at higher risk for opioid-induced respiratory depression (OIRD) compared to the general population. The aims of this systematic review were to summarize current evidence with respect to perioperative OIRD, changes in sleep-disordered breathing, and alterations in pain and opioid sensitivity in patients with OSA. A systematic literature search of studies published between 1946 and October 2017 was performed utilizing the following databases: Medline, ePub Ahead of Print/Medline In-process, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed-NOT-Medline and ClinicalTrials.Gov. Of 4321 initial studies, 40 met the inclusion criteria. The Oxford level of evidence was assessed. Overall, high-quality evidence on the comparative impact of acute opioid analgesia in OSA versus non-OSA patients is lacking. The current body of evidence is burdened by significant limitations including risk of bias and large heterogeneity among studies with regard to OSA severity, perioperative settings, outcome definitions, and the presence or absence of various perioperative drivers. These factors complicate an accurate interpretation and robust analysis of the true complication risk. Nevertheless, there is some consistency among studies with regard to a detrimental effect of opioids in the presence of OSA. Notably, the initial 24 hours after opioid administration appear to be most critical with regard to life-threatening OIRD. Further, OSA-related increased pain perception and enhanced opioid sensitivity could predispose patients with OSA to a higher risk for OIRD without overdosing. While high-quality evidence is needed, retrospective analyses indicate that critical, life-threatening OIRD may be preventable with a more cautious approach to opioid use, including adequate monitoring.