Mental health and suicide-related harms resulting from prescription opioid tapering are poorly documented and understood. Six health systems contributed opioid prescribing data from January 2016 to April 2020. Patients 18 to 70 years old with evidence of opioid tapering participated in semi-structured interviews. Individuals who experienced suicide attempts were oversampled. Family members of suicide decedents who had experienced opioid tapering were also interviewed. Interviews were analyzed using thematic analysis. The study participants included 176 patients and 16 family members. Patients were 68% female, 80% White, and 15% Hispanic, mean age 58. All family members were female spouses of White, non-Hispanic male decedents. Among the subgroup (n = 60) who experienced a documented suicide attempt, reported experiencing suicidal ideation during tapering, or were family members of suicide decedents, 40% reported that opioid tapering exacerbated previously recognized mental health issues, and 25% reported that tapering triggered new-onset mental health concerns. Among participants with suicide behavior, 47% directly attributed it to opioid tapering. Common precipitants included increased pain, reduced life engagement, sleep problems, withdrawal, relationship dissolution, and negative consequences of opioid substitution with other substances for pain relief. Most respondents reporting suicide behavior felt that the decision to taper was made by the health care system or a clinician (67%) whereas patients not reporting suicide behavior were more likely to report it was their own decision (42%). This study describes patient-reported mental health deterioration or suicide behavior while tapering prescription opioids. Clinicians should screen for, monitor, and treat suicide behavior while assisting patients in tapering opioids. PERSPECTIVE: This work describes changes in patient-reported mental health and suicide behavior while tapering prescription opioids. Recommendations for improving care include mental health and suicide risk screening during and following opioid tapering.