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Background: The efficacy of methadone in reducing morbidity and mortality associated with opioid use disorder is supported by a wealth of evidence, yet methadone retention is often poor. While crystal methamphetamine (methamphetamine) use has been recently increasing in many countries, the effect of frequency of methamphetamine use on methadone discontinuation has not been investigated. We aimed to examine whether frequency of methamphetamine use is associated with increased rates of methadone discontinuation among individuals on methadone. Design: Two harmonized ongoing open prospective cohort studies of community-recruited people who use illicit drugs with semi-annual follow-ups between 2014 and 2018. Setting: Vancouver, Canada. Participants: A community recruited sample of people who use drugs. Intervention: A time-varying variable of self-reported methamphetamine use frequency within the past six months. Measurements: The primary outcome was time to discontinuation of methadone, defined as reporting not being on methadone at the time of a follow-up interview during the study period. We employed multivariable extended Cox regression analysis to examine the relationship between frequency of methamphetamine use and time to methadone discontinuation after adjusting for potential confounders. Findings: Of 875 eligible participants who contributed 2319 person-years of follow-up, 284 (32.5 %) discontinued methadone at least once during follow-up and 135 (15.4 %) reported more than weekly methamphetamine use at study baseline. In a multivariate analysis, in comparison to no use, ≥weekly use of methamphetamine remained independently associated with methadone discontinuation (adjusted hazard ratio [aHR] = 1.38, 95 % CI = 1.03–1.85). Conclusions: A significant proportion of participants on methadone in this study reported more than weekly crystal methamphetamine use, which was associated with an increased risk of methadone discontinuation. Closer follow up, education, and treatment of methamphetamine use may be needed for this group to improve methadone retention.