Aim: The aim of this study was to estimate how ongoing stimulant use affects return to illicit opioid use after initiation onto medication for opioid use disorder (MOUD). Design: This was a secondary analysis of pooled data from two clinical trials comparing buprenorphine (BUP‐NX) and extended‐release naltrexone (XR‐NTX). Setting: Thirteen opioid treatment programs and HIV clinics across 10 states in the United States from 2014 to 2019 took part in this study. Participants: A total of 528 participants who initiated MOUD as part of trial participation were included. Nearly half (49%) were between 30 and 49 years of age, 69% were male and 66% were non‐Hispanic White. Measurements The primary outcome was first self‐reported day of non‐prescribed opioid use following MOUD initiation, and the exposure of interest was daily stimulant use (methamphetamine, amphetamines or cocaine). Both were defined using time‐line follow‐back. Among participants reporting at least 1 day of illicit opioid use, we also examined relapse to ongoing use, defined as (1) 7 days of continuous opioid use or (2) 4 consecutive weeks with self‐reported opioid use, one or more positive urine drug screens (UDS) for opioids or one or more missing UDS. Findings Forty‐seven per cent of participants reported stimulant use following MOUD initiation, 58% returned to illicit opioid use and 66% of those relapsed to ongoing use. Stimulant use was strongly associated with increased risk of misusing opioids after MOUD initiation when measured daily [adjusted hazard ratio (aHR) = 9.23, 95% confidence interval (CI) = 6.80–12.50, P < 0.001] and over a 7‐day period (aHR = 1.27 for each additional day, CI = 1.18–1.37, P < 0.001). Using stimulants weekly or more often was associated with increased likelihood of relapse to ongoing opioid use compared with less than weekly or no stimulant use (adjusted odds ratio = 2.30, CI = 1.05–5.39, P = 0.044). Conclusions: People initiated on medication for opioid use disorder who subsequently use stimulants appear to be more likely to return to and continue using non‐prescribed opioids compared with those without stimulant use. The association appears to be stronger among patients who initiate buprenorphine compared with those who initiate extended‐release naltrexone. [ABSTRACT FROM AUTHOR]