Abstract Persons with opioid use disorder (OUD) enrolled in methadone maintenance programs continue to have smoking prevalence rates of 80-90% and high rates of tobacco-related morbidity and mortality. Multiple clinical trials of pharmacotherapy have documented that methadone-maintained smokers (MMS) have very low smoking cessation rates. These low rates of successful quitting and the significant health consequences of smoking combustible cigarettes (CC), it is critical to identify harm-reduction strategies in this at-risk population. Electronic cigarette (EC) use has grown rapidly and substituting combustible cigarettes with EC use may decrease health risks in MMS. We propose to take a first step in examining the risks and benefits associated with EC use among MMS. Of particular interest would be the health effects of ECs among MMS because of MMS’ difficulty with prolonged CC quitting, the severity of their nicotine dependence, greater tobacco demand, and the precedent of harm reduction wherein opioid users substitute a lower risk opioid (methadone) for illicit drug use. Thus, we are proposing to utilize a fourth generation EC (JUUL) to examine behavioral and health biomarker changes of MMS smokers interested in switching from combustible cigarettes to ECs. Given the continuing popularity of ECs, there is an urgent need to improve our understanding of both the potential benefits and risks of EC use in this vulnerable population. We propose to conduct a 4-year randomized clinical trial of 240 MMS who are interested in switching to another nicotine alternative. Participants will be randomly assigned (2:1) to either 6-weeks of EC (JUUL; n=160) or to 6-weeks of nicotine replacement therapy (NRT; in the form of nicotine lozenges; n=80). Participants in both conditions will attend weekly assessment sessions where smoking status is confirmed. At the end of 6 weeks, we will assess biomarkers of total nicotine intake and tobacco toxicant exposure, respiratory symptoms, and spirometry-determined lung functioning as well as rates of complete switching, EC, NRT, and CC use (including dual use), tobacco demand and self-efficacy for quitting CC. Continued use of EC, NRT, and CC will be examined at the 12- and 24-week follow-ups. This study will be the first to test the potential behavioral and health effects of ECs in smokers with opioid use disorder, a population that is highly dependent on nicotine, highly vulnerable to smoking-related morbidity and mortality, and searching for novel methods to lower smoking-related risks.