Pain is experienced by most patients with cancer and opioids are a cornerstone of cancer pain management. Our objectives were (1) to identify patterns or trajectories of long-term opioid therapy (LTOT) and their correlates among patients with and without cancer and (2) to assess the association between trajectories and risk for opioid overdose, considering the potential moderating role of cancer. We conducted a retrospective cohort study among Veterans in the Veterans Health Administration (VHA) electronic health record database with incident LTOT with and without cancer (N=44,351; N=285,772, respectively) between 2010-2017. Using latent growth mixture modeling and Cox Proportional Hazards modeling, we investigated the relationship between trajectory of LTOT and all ICD-9 and 10-defined accidental and intentional opioid-related overdose events. Trajectories of opioid receipt observed in patients without cancer and replicated in patients with cancer were: low-dose, low-dose/de-escalating trend, moderate-dose, moderate-dose/escalating trend, and high-dose/escalating trend. Time to first overdose was significantly predicted by higher-dose and escalating trajectories; the two low-dose trajectories conferred similar, lower risk. Conditional hazard ratios (99% CI) for the moderate-dose and moderate-dose/escalating and high-dose/escalating trends were 1.84 (1.19, 2.85), 2.65 (1.63, 4.32), and 2.25 (1.27, 3.96), respectively. Effects of trajectories on time to overdose did not differ presence of cancer. Inferences were replicated when restricting the cancer sample to patients with stage 3 or 4 cancer at cohort entry. Patients with cancer face opioid overdose risks like patients without cancer. Clinicians and researchers alike should consider this when counseling patients and developing inclusion criteria for studies of LTOT. Future studies should seek to expand our knowledge about opioid risk in patients with cancer, and how to address it. Grant support from Department of Veterans Affairs (VA) Service Directed Research project SDR 15-461. Pain is experienced by most patients with cancer and opioids are a cornerstone of cancer pain management. Our objectives were (1) to identify patterns or trajectories of long-term opioid therapy (LTOT) and their correlates among patients with and without cancer and (2) to assess the association between trajectories and risk for opioid overdose, considering the potential moderating role of cancer. We conducted a retrospective cohort study among Veterans in the Veterans Health Administration (VHA) electronic health record database with incident LTOT with and without cancer (N=44,351; N=285,772, respectively) between 2010-2017. Using latent growth mixture modeling and Cox Proportional Hazards modeling, we investigated the relationship between trajectory of LTOT and all ICD-9 and 10-defined accidental and intentional opioid-related overdose events. Trajectories of opioid receipt observed in patients without cancer and replicated in patients with cancer were: low-dose, low-dose/de-escalating trend, moderate-dose, moderate-dose/escalating trend, and high-dose/escalating trend. Time to first overdose was significantly predicted by higher-dose and escalating trajectories; the two low-dose trajectories conferred similar, lower risk. Conditional hazard ratios (99% CI) for the moderate-dose and moderate-dose/escalating and high-dose/escalating trends were 1.84 (1.19, 2.85), 2.65 (1.63, 4.32), and 2.25 (1.27, 3.96), respectively. Effects of trajectories on time to overdose did not differ presence of cancer. Inferences were replicated when restricting the cancer sample to patients with stage 3 or 4 cancer at cohort entry. Patients with cancer face opioid overdose risks like patients without cancer. Clinicians and researchers alike should consider this when counseling patients and developing inclusion criteria for studies of LTOT. Future studies should seek to expand our knowledge about opioid risk in patients with cancer, and how to address it. Grant support from Department of Veterans Affairs (VA) Service Directed Research project SDR 15-461.