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Objective: This study was designed to examine the association between physical activity (PA) and depression among adult prescription opioid users., Method: Data of adults who recently took prescription opioids were collected from NHANES 2007-2018. Participants were divided into two groups according to whether PA in each domain was ≥600 MET-min/week. According to weekly activity frequency, recreational physical activity (RPA) was divided into inactivity, insufficient activity, weekend warrior (WW), and regular activity. PHQ-9 scores ≥10 were identified as depression., Results: RPA of ≥600 MET-min/week was associated with a 40% (OR: 0.60, 95%CI: 0.38-0.96, P = 0.032) reduction in the risk of depression. Restricted Cubic Spline plots found a nonlinear dose-response relationship between RPA and depression (P = 0.045), and the turning point of depression risk was around 600 MET-min/week. There was no significant difference in the risk of depression between the WW and inactivity groups (OR: 0.65, 95%CI: 0.25-1.72, P = 0.382). The regular activity group had an 45% (OR: 0.55, 95%CI: 0.31-0.99, P = 0.046)lower risk for depression than the inactivity group., Conclusion: Only regular RPA is associated with a reduced risk of depression, and RPA showed a nonlinear dose-response relationship. The antidepressant effect of the WW is not significant., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)