Background: Opioid analgesia has an important role in treating cancer pain but can place survivors at risk for long-term adverse effects, including misuse, abuse, and overdose. While opioid use has been studied in surgical oncology patients, little is known about long-term use and outcomes for patients with hematologic malignancies who primarily receive non-surgical treatment. We evaluated the association between opioid use during lymphoma treatment and persistent high-risk opioid use. Methods: We conducted a retrospective cohort study using IBM Watson Health MarketScan Commercial Claims and Encounters Data from 2000-2019, containing claims for employer-sponsored privately insured individuals in the US. We identified opioid-naïve adults age 18-64 years at their first diagnosis of Hodgkin (HL) or Non-Hodgkin lymphoma (NHL) who had outpatient cancer therapy lasting 90-240 days (including ≥3 episodes of outpatient chemotherapy). Using outpatient pharmacy claims, we categorized each patient’s opioid exposure during cancer treatment to no exposure, moderate [1-7 days supply], or high [ > 7 days supply]. Follow-up began 60 days after patients’ final cancer treatment and continued up to 365 days or until an outcome or censoring event. High-risk opioid use was defined as ≥120 days cumulative supply, ≥3 consecutive months of opioid prescriptions, or a prescription with ≥90 morphine milligram equivalents per day. We used time-to-event methods to estimate cumulative incidence and hazard ratios across exposure groups. Results: There were 4380 opioid-naïve lymphoma patients in the cohort. 42.5% had HL and 57.5% had NHL. Median age at diagnosis was 46 years (IQR 32-56) and median treatment duration was 147 days (IQR 112-166). 55.0% of patients were male. During cancer treatment, 42.8% of patients had no opioid exposure, 28.1% had moderate, and 29.1% had high. Among the no-opioid-exposure group, the 1-year cumulative incidence of high-risk opioid use was 1.7%. Compared to this no-exposure group, the hazard ratios for moderate and high exposure were 2.6 (95% CI 1.5-4.6) and 9.0 (95% CI 5.6-14.4), respectively, after adjustment for cancer treatment duration, age, cancer type, and calendar time. A sensitivity analysis comparing patients diagnosed 2000-2009 vs. 2010-2019 found that hazard ratios remained consistent between the two time periods; however, there was a decrease in the absolute incidence of high-risk opioid use by approximately half. Conclusions: In this cohort study of opioid-naïve lymphoma patients, higher opioid exposure during cancer treatment was associated with a higher likelihood for persistent high-risk opioid use in the year following cancer treatment. The absolute incidence of high-risk opioid use decreased over time and may be due to increased awareness of the opioid epidemic. Close clinical follow-up in the post-treatment period may be warranted for patients at high risk of adverse outcomes.