Background and aims Pharmaceutical opioid prescription rates are increasing globally, however knowledge of their long-term effects on mental health, in particular depression remains limited. This study aimed to identify factors associated with the onset of depression post-opioid use that differ to factors associated with depression post-pain. Method Participants (N=1 418) were a national sample prescribed opioids for chronic non-cancer pain. Age at onset of depression, pain and commencement of opioid medications were collected via structured interview. Results Six in 10 (61%) reported lifetime depression; of those, almost half developed depression after pain and after they started opioid medications (48%). Variables associated with post-opioid depression included lower pain self-efficacy and poorer social support, younger onset of opioid use, and difficulties and concerns with opioid medications. Conclusions The findings highlight the importance of monitoring for the emergence of mood dysfunction, particularly for those starting opioids for pain at a younger age, and consideration of psychological treatments that address self-efficacy that appears to be associated with post-opioid depression.