Fourth-generation nicotine salt pod system (NSPS) electronic cigarettes (e-cigarettes) are the leading class of e-cigarettes. They contain high nicotine concentrations, which may facilitate switching among smokers, but could also lead to increased exposure to nicotine and biomarkers of potential harm. African American and Latinx smokers experience significant tobacco-related health disparities. The potential of NSPS e-cigarettes to reduce smoking-related harm among these groups is unknown. To compare the harm reduction potential of NSPS e-cigarette vs combustible cigarettes. This unblinded randomized clinical trial compared 6 weeks of e-cigarette use vs cigarettes as usual from to 2018 to 2019 among smokers in the San Diego, California, and Kansas City, Missouri, areas. Participants included African American and Latinx adult combustible cigarette smokers who smoked at least 5 cigarettes/d on at least 25 of the past 30 days for at least 6 months and were interested in switching to e-cigarettes. Data were analyzed from September 18, 2019, to September 4, 2020. 6 weeks of e-cigarette use in a choice of pod flavors (5% nicotine) along with brief education, training, and action planning to completely switch to e-cigarettes from combustible cigarettes. The control group smoked combustible cigarettes as usual. The primary outcome was reduction in urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentration at week 6. Secondary outcomes were change in urinary cotinine, expired carbon monoxide (CO), respiratory symptoms, lung function, blood pressure, past 7-day consumption of combustible cigarettes, and switching rates (e-cigarette group only) at weeks 2 and 6. This study included 186 participants, including 92 African American participants and 94 Latinx participants. The mean (SD) age was 43.3 (12.5) years, and 75 (40.3%) were women. Participants smoked a mean (SD) of 12.1 (7.2) cigarettes/d on 6.8 (0.6) d/wk at baseline. A total of 125 participants were randomized to the e-cigarette group and 61 were randomized to the control group. At baseline, median (interquartile range) NNAL was 124 (45-197) pg/mL in the e-cigarette group and 88 (58-197) pg/mL in the control group. At week 6, the e-cigarette group had significantly greater reductions in NNAL (relative risk [RR], 0.36 [95% CI, 0.23-0.54]; P < .001), CO (RR, 0.53 [95% CI, 0.42-0.68]; P < .001), respiratory symptoms (RR, 0.63 [95% CI, 0.47-0.85]; P = .002), and number of cigarettes smoked in the past 7 days among those still smoking (RR, 0.30 [95% CI, 0.20-0.43]; P < .001) than the control group and maintained their cotinine levels (RR, 0.80 [95% CI, 0.58-1.10]; P = .17). Lung function and diastolic and systolic blood pressure remained unchanged and did not differ between groups. For participants randomized to receive e-cigarettes, 32 participants (28.1%) were exclusively using e-cigarettes at week 6, while 66 participants (57.9%) were dual using and 16 participants (14%) resumed exclusively using cigarettes. These findings suggest that e-cigarettes may be an inclusive harm reduction strategy for African American and Latinx smokers. ClinicalTrials.gov Identifier: NCT03511001.