OBJECTIVE The aim of this study was to determine the frequency of opioid-induced neurotoxicity (OIN) in cancer patients receiving oral controlled-release oxycodone and to define risk factors for OIN. METHODS This was a single-center, retrospective study of hospitalized adult cancer patients receiving oral controlled-release oxycodone between April 1, 2013, and April, 30, 2020. The onset of OIN within 30 days after oxycodone initiation in the study patients was investigated. OIN was defined as any of the following: delirium, hallucinations (visual or auditory), seizure, myoclonus, hyperesthesia, and excessive somnolence. Multivariate logistic regression analysis was performed to identify risk factors for OIN in patients receiving oxycodone. RESULTS In total, 520 patients were included in this study. The number of patients with OIN was 65 (12.5%). The median time until onset of OIN after oxycodone initiation was 7.5 days. Multivariate logistic regression analysis revealed that age ≥ 65 years (OR = 2.74, 95% CI [1.30-5.78], p = 0.008), total bilirubin ≥ 1.3 mg/dL (OR = 4.85, 95% CI [2.13-11.0], p < 0.001), and concomitant use of pregabalin or mirogabalin (OR = 3.11, 95% CI [1.47-6.61], p = 0.003) were significant independent risk factors for OIN. CONCLUSIONS Age ≥ 65 years, liver dysfunction, and concomitant use of pregabalin or mirogabalin were independent risk factors for OIN in patients receiving oxycodone. Patients with these risk factors who are receiving oxycodone should be monitored for OIN, especially early in the administration of oxycodone.