Background Depression contributes to persistent opioid analgesic use (OAU). Treating depression may increase opioid cessation. Aims To determine if adherence to antidepressant medications (ADMs) v. non-adherence was associated with opioid cessation in patients with a new depression episode after >90 days of OAU. Method Patients with non-cancer, non-HIV pain (n = 2821), with a new episode of depression following >90 days of OAU, were eligible if they received =1 ADM prescription from 2002 to 2012. ADM adherence was defined as >80% of days covered. Opioid cessation was defined as =182 days without a prescription refill. Confounding was controlled by inverse probability of treatment weighting. Results In weighted data, the incidence rate of opioid cessation was significantly (P = 0.007) greater in patients who adhered v. did not adhered to taking antidepressants (57.2/1000 v. 45.0/1000 person-years). ADM adherence was significantly associated with opioid cessation (odds ratio (OR) = 1.24, 95% CI 1.05-1.46). Conclusions ADM adherence, compared with non-adherence, is associated with opioid cessation in non-cancer pain. Opioid taper and cessation may be more successful when depression is treated to remission.