Abstract The majority of smokers try to quit each year, and the majority of quit attempts fail, even when the most effective FDA-approved pharmacotherapies are used. Non-combustible tobacco products emit fewer harmful chemicals than cigarettes, and thus for smokers who cannot quit smoking, switching completely to a less harmful product is likely to improve their health. For smokers who have failed to quit with traditional methods, trying to switch to a less harmful product may be more likely to help them stop smoking than trying to quit using tobacco altogether repeatedly with pharmacotherapy. The proposed trial evaluates the potential of non-cigarette tobacco products to serve as harm reduction tools for current smokers who have already tried, and failed, to quit with traditional methods. Current smokers who failed to quit with FDA-approved pharmacotherapy within the past year (N=225) will be randomly assigned to either 1) switch completely to a non-cigarette tobacco product (Switch Group, n=150), or 2) try to quit again using pharmacotherapy (Meds Group, n=75). Participants will choose among a limited menu of products or medications they would like to receive (maximizing external validity) and select a Target Switch / Quit Date on which they will stop smoking. Participants in the Switch Group will choose between two non-cigarette products that deliver sufficient nicotine and are appealing to adult smokers: e-cigarettes, the most commonly used non-cigarette tobacco product, or heated tobacco products, a novel tobacco product recently approved for sale by FDA as modified risk exposure compared to cigarettes. Both product classes, while not safe, emit fewer harmful chemicals compared to cigarettes. Participants in the Meds Group will choose between the two most effective pharmacotherapies available: varenicline or combination transdermal nicotine replacement therapy and short-acting nicotine lozenge. Participants in the Switch or Meds groups will receive a 9-week supply; broken down as: 1-week to use ad libitum while continuing to smoke, and 8-weeks to use as instructed following a Target Switch or Quit Date. The primary outcome is biochemically-confirmed abstinence from cigarette smoking at the 6-month follow-up, and secondary outcomes include smoking reduction > 50%, longest quit attempt duration, biomarkers of nicotine, smoke, and toxicant exposure, and changes in respiratory symptoms. The proposed trial addresses a highly significant research question using a rigorous design and is supported by a strong investigative team. The trial is in line with priorities within NOT-OD-22-023 including “Harm reduction studies that involve switching from combustible cigarettes to ENDS [or heated tobacco products].”