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Cancer patients may be particularly vulnerable to the deleterious effects of prolonged opioid use. The authors explored the factors that influence postoperative opioid prescription fills among women following postmastectomy reconstruction.Using the Truven Health MarketScan Research Databases, the authors identified a cohort of 4113 opioid-naive patients undergoing mastectomy and immediate breast reconstruction between January of 2010 and August of 2014. Outcomes included average daily oral morphine equivalents and the incidence of prolonged opioid fills (between 90 and 120 days after surgery). Using multivariable regression, the authors examined the effect of patient demographic characteristics, reconstructive technique, comorbid medical and psychiatric conditions, and postoperative complications on outcome variables.In this cohort, 90 percent of patients filled opioid prescriptions perioperatively, and 10 percent continued to fill prescriptions beyond 3 months after surgery. Patients with depression were more likely to fill prescriptions of higher average daily oral morphine equivalents (74.2 mg versus 58.3 mg; p < 0.01), and patients with anxiety were more likely to fill opioids for prolonged periods (13.4 percent versus 9.1 percent; p < 0.01). Patients undergoing autologous free flap reconstruction were less likely to fill prescriptions for a prolonged period following surgery (5.9 percent versus 10.2 percent; p < 0.001).Prescription opioid fills are common following breast reconstruction, and 10 percent of all patients continue to fill opioid prescriptions beyond 3 months after surgery. Prolonged fills are influenced by both patient factors and surgical procedure, and attention should be directed toward identifying opioid alternatives when possible.Risk, III.