["Addiction, EarlyView. ", "\nAbstract\n\nAims\nTo assess whether higher wattage e‐cigarettes (HWe), with improved nicotine delivery, enhance complete substitution compared with lower wattage e‐cigarettes (LWe) and whether complete switching lowers exposure to a cigarette‐derived lung carcinogen, using urinary 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol (NNAL) as a biomarker.\n\n\nDesign\nA 3‐arm randomized controlled trial with a 12‐week treatment period and follow‐ups at 26 and 52 weeks. Participants were enrolled from June 2017 to December 2022, with all visits completed by March 2023.\n\n\nSetting\nAcademic medical centers in the United States.\n\n\nParticipants\n372 adults who smoked and were not interested in quitting [mean age = 40 years; standard deviation (SD) = 11.0; 63% female; mean cigarettes per day = 17; SD = 8.9] were randomized and comprised the analytic sample.\n\n\nIntervention\nA 12‐week supply of HWe, LWe or usual brand cigarettes (UBC).\n\n\nMeasurements\nThe primary outcome was between‐group differences in complete substitution rates at week 12, defined as self‐reported smoking of 1 or fewer cigarettes in the past 7 days [confirmed by exhaled carbon monoxide (eCO) < 4 ppm], with missing data imputed as smoking, and self‐reported use of e‐cigarettes during the 7‐day period. Additional outcomes included urinary NNAL through week 12.\n\n\nFindings\nAt 12 weeks, complete substitution rates were 6.0% (8 of 134) with HWe and 9.0% (12 of 133) with LWe, with no statistically significant between‐group difference. Complete substitution rates were 3.7% (HWe) vs. 9.0% (LWe) at 26 weeks, and 4.5% vs. 5.3% at 52 weeks, with no statistically significant between‐group differences. Among those who completely switched, mean NNAL levels decreased over 12 weeks with both LWe [mean decrease: 2.4 pmol/mg creatinine; 95% confidence interval (CI) = 1.2–3.7; P = 0.002] and HWe (mean decrease: 2.3 pmol/mg creatinine; 95% CI = 1.1–3.6; P = 0.002).\n\n\nConclusions\nProvision of higher and lower wattage e‐cigarettes to adults who smoked and were not interested in quitting resulted in comparable substitution rates. Complete switching from cigarettes to higher and lower wattage e‐cigarettes reduced urinary 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol.\nTrial Registration: NCT03113136 (ClinicalTrials.gov).\n\n"]