ABSTRACT: Background: Opioids are commonly prescribed to hospitalized adults to promote adequate pain relief, yet they can cause potentially fatal respiratory depression. Aim: The aim of this study was to examine the risk factors for the development of severe opioid-induced respiratory depression (OIRD) in hospitalized adults to ensure adequate monitoring of high-risk patients. Methods: A retrospective case-control study was conducted using data from the medical records of a university-affiliated hospital in Canada. Cases were eligible if they were adults (≥18 years old) and received opioid analgesia within 24 h of naloxone administration for respiratory depression. Controls had the same eligibility criteria, except for respiratory depression and naloxone administration. The case-control ratio was 1:1, and they were matched based on sex, type of unit, opioid molecule and the presence/absence of medication errors. Results: A total of 133 cases and 133 controls were included. Following cumulative risk factor analysis, renal failure (odds ratio [OR] = 2.176, 95% confidence interval [CI], 1.021-4.640, P = 0.044), the first 24 h of opioid administration (OR = 1.899, 95% CI, 1.090-3.309, P = 0.024), concomitant central nervous system (CNS) depressants (OR = 1.785, 95% CI, 1.023-3.113, P = 0.041), and increasing age (OR = 1.019, 95% CI, 1.002-1.035, P = 0.028) were positively associated with severe OIRD. Conclusions: Some adult hospitalized patients were at higher risk of experiencing severe OIRD, such as those with renal failure, those in their first 24 h of opioid administration, those receiving CNS depressants in addition to opioids, and those with an advanced age. These results will assist with the screening of patients at higher risk for severe OIRD, which is key to implementing appropriate monitoring and enhancing the safety of opioid use in hospital settings.