© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Background: Wax microsphere bound oxycodone was developed as an abuse-deterrent opioid and maintains a similar pharmacokinetic profile whether administered with or without an intact capsule. We hypothesized that microsphere oxycodone could be utilized for extended release analgesia in patients undergoing radiation (RT) for head-and-neck cancer (HNC) and would not need to be discontinued due to dysphagia or gastrostomy tube dependence. Methods and materials: We performed a prospective trial that enrolled participants > 18 years with histologically confirmed HNC who were scheduled to receive RT. Analgesia was prescribed in accordance with the WHO pain ladder. Microsphere oxycodone was initiated when total daily opioid dose exceeded 30 mg of morphine sulfate equivalent and was titrated weekly during RT. Pain level and effect on quality of life were assessed using the Brief Pain Inventory. The primary feasibility endpoint was frequency of microsphere oxycodone discontinuation within 3 months of RT for reasons other than pain resolution. Results: Twenty-six eligible patients were enrolled. Microsphere oxycodone was initiated in 16 (61.5%) patients. Six (23.1%) patients utilized a gastrostomy tube to administer microsphere oxycodone during all or part of RT. Microsphere oxycodone was discontinued in 1 (7.6%) patient due to perceived inefficacy. No patients were discontinued due to toxicity or difficulty with administration. Ratings for average pain was 3.1 (± 3.4) at enrollment, 4.0 (± 2.4) at week 6 of RT, and 1.8 (± 2.2) at 3-month follow-up. Conclusions: These results support the feasibility and safety of microsphere oxycodone for extended release analgesia among patients with HNC undergoing RT.