Importance: Smokers with chronic obstructive pulmonary disease (COPD) have particular difficulty quitting. Long-term nicotine replacement therapy (LT-NRT) might offer a strategy for reducing harm from cigarettes and provide a pathway for later cessation., Objective: To compare the effect of LT-NRT vs standard smoking cessation (SSC) on exposure to cigarette smoke, harm related to smoking, and cessation among smokers with COPD., Design, Setting, and Participants: This unblinded, randomized clinical trial recruited smokers who self-reported a diagnosis of COPD at any level of readiness to quit from May 23, 2014, through November 30, 2015. The 12-month follow-up was completed December 6, 2016. Patients were recruited at a clinical research unit of an academic medical center. Analysis was based on intention to treat and performed from March 8 through November 30, 2017., Interventions: Standard smoking cessation treatment included 10 weeks of NRT and 4 follow-up counseling sessions for those willing to make a quit attempt. Long-term NRT included 12 months of NRT and 6 follow-up counseling sessions regardless of initial willingness to quit. Overall, 198 patients were randomized to SSC, and 197 were included in the primary analysis; 200 patients were randomized to LT-NRT, and 197 were included in the primary analysis., Main Outcomes and Measures: The primary outcome was 7-day abstinence verified by carbon monoxide (CO) levels at 12 months. Secondary outcomes included cigarettes smoked per day (CPD), exposure to CO, urinary excretion of 4-methylnitrosamino-1-3-pyridyl-1-butanol (NNAL) (a smoking-related carcinogen), and adverse events., Results: Among 398 patients who were randomized (59.8% female; mean [SD] age, 56.0 [9.3] years), the mean (SD) CPD was 23.1 (12.3). Twelve-month follow-up was completed by 373 participants (93.7%), and 394 (99.0%) were included in the primary analysis. At 12 months, CO-verified abstinence occurred in 23 of 197 participants (11.7%) in the SSC arm and 24 of 197 (12.2%) in the LT-NRT arm (risk difference, 0.5%; 95% CI, -5.9% to 6.9%). Continuing smokers in the SSC and LT-NRT arms had similar, significantly reduced harms caused by smoking, including cigarette consumption by 12.4 and 14.5 CPD, respectively, exhaled CO level by 5.5 and 7.8 ppm, respectively, and mean urinary NNAL excretion by 21.7% and 23.0%, respectively. In multivariate analyses, continuing smokers with greater adherence to NRT experienced less reduction in NNAL exposure. The frequency of major adverse cardiac events was similar in both groups., Conclusions and Relevance: Similar rates of cessation and similar reductions in exposure to tobacco smoke resulted with LT-NRT and SSC. Among continuing smokers, ongoing use of NRT was not associated with reductions in smoke exposure., Trial Registration: ClinicalTrials.gov Identifier: NCT02148445.