Background: The COVID-19 pandemic has been associated with increased opioid prescribing. It is not known if perceived COVID-19 related stress is associated with increased odds of long-term opioid use. Objective: To determine if greater COVID-19-related stress and worsening pain attributed to the pandemic was associated with LTOT over a 6-month observation period. Design: Longitudinal cohort. Participants: Patients (n=477) from two midwestern health care systems, with any acute or chronic non-cancer pain, starting a new period of 30–90-day prescription opioid use, were invited to participate in the Prescription Opioids and Depression Pathways Cohort Study, a longitudinal survey study of pain, opioid use, and mental health outcomes. Main Measures: Baseline and 6-month follow-up assessments were used to measure the association between perceived COVID-19 stressors, the perception that pain was made worse by the pandemic and the odds of persistent opioid use, i.e., remaining a prescription opioid user at 6-month follow-up. Multivariate models controlled for demographics, opioid dose, and change in pain characteristics, mental health measures, and social support. Key Results: Participants were, on average, 53.9 (±11.4) years of age, 67.1% White race, and 70.9% female. The most frequently endorsed COVID-19 stressor was “worry about health of self/others” (85.7% endorsed) and the least endorsed was “worsened pain due to pandemic” (26.2%). After adjusting for all covariates, “worsened pain due to pandemic” (OR=2.88; 95%CI: 1.33–6.22), change in pain interference (OR=1.20; 95%CI: 1.04–1.38), and change in vital exhaustion (OR=0.90; 95%CI: 0.82–0.99) remained significantly associated with persistent opioid use. Conclusions: Patients who attribute worsening pain to the COVID-19 pandemic are more likely to be persistent opioid users. Further research is warranted to identify mechanisms underlying this association. Clinicians may consider discussing pain in the context of the pandemic to identify patients at high risk for persistent opioid use.