PURPOSE/OBJECTIVE(S): Symptom management is critical during radiation therapy (RT) for head and neck cancer (HNC). Worse pain during RT has been associated with worse treatment tolerance, weight loss, and worse quality of life (QoL). This study further explored the relationship between pain control, weight loss, and QoL in a prospective cohort of patients receiving RT for HNC. MATERIALS/METHODS: This study was a secondary analysis of a clinical trial of microsphere oxycodone (NCT03317730) during RT for locally advanced HNC. Participants had RT dose > 50 Gy, ECOG 0-2, and no known history of substance abuse. Analgesia was prescribed in accordance with the WHO Pain Ladder, but the extended-release opioid option was limited to microsphere oxycodone. QoL was assessed with the Brief Pain Inventory and EORTC HN-35 forms at baseline and 1- and 3-months post-RT. Correlations were assessed using Pearson's r and differences in means were determined with the independent samples T-test. Analysis was performed using IBM SPSS software. RESULTS: Responses were available from participants at 1 month post-RT (n = 23) and at 3 months post-RT (n = 21). At baseline, BMI positively correlated with pain control. In addition, at baseline, worst pain correlated with amount of pain interfering with enjoying life as well as with the ability to eat solid foods (Table). Change in worst 24-hour pain from enrollment to 1- and 3-months post-RT was significantly associated with change in ability to enjoy life due to pain. At 3-months post-RT, change in worst pain negatively correlated with overall ability to enjoy life and ability to eat solid food. Change in BMI correlated with change in relief with pain medication at 1-month and 3-months post-RT. No significant difference in pain relief was noted when considering men vs women (2.06 vs 0.33, P = 0.3). CONCLUSION: This study supports the hypothesis that response to pain medication is associated with change in weight during and shortly after completion of RT. Pain levels were significantly correlated with QoL, particularly the ability to enjoy life and eat food at both 1- and 3-months post-RT. Ongoing research is needed to better elucidate the relation between pain control and patient outcomes, and to develop new interventions to promote QoL among patients with HNC.