Adults with mood disorders frequently use prescription opioids. The factors associated with this increased use remain unclear. We used the Medical Expenditure Panel Surveys from 2005 to 2011 to measure the association of mood disorders with new opioid use and the transition to longer-term opioid use for a variety of pain conditions before and after controlling for patient characteristics and clinical disability. We analyzed 33,450 adults with likely acute or potentially chronic pain conditions who were not using opioids at baseline. Among respondents with likely acute pain conditions, those with mood disorders initiated opioids more frequently for that pain condition compared with those without mood disorders (19.3%, vs 17.2%, P = 0.01). After initiation, they also transitioned to longer-term opioid therapy more frequently (11.7% vs 5.3%, P < 0.01). Among respondents with potentially chronic pain conditions, adults with mood disorders initiated opioid therapy more frequently for their chronic pain condition (11.5% vs 9.2%, P < 0.01) and transitioned to longer-term therapy more frequently (36.8% vs 19.9%, P < 0.01). After adjusting for sociodemographics and clinical disability, there was no association between mood disorders and new opioid use for likely acute (adjusted odds ratio [aOR] 1.05 [0.92-1.20]) or potentially chronic pain (aOR 0.91 [0.80-1.03]). However, there remained a strong association between mood disorders and the transition to longer-term opioid use for likely acute (aOR 1.77 [1.15-2.72]) and potentially chronic pain (aOR 1.95 [1.42-2.68]). Targeting the transition to longer-term opioid use may help clinicians reduce potentially inappropriate opioid prescriptions in this high-risk population.