PROJECT SUMMARY Individuals who smoke cigarettes with obesity (SWO) carry a disproportionate burden of tobacco-related disease and death due to the interactive effects of smoking and excess weight. Smoking increases insulin resistance and central adiposity (i.e., abdominal obesity), increasing the risk of metabolic syndrome, diabetes, and cardiovascular disease (CVD). Consequently, SWO have 10x the risk of mortality from CVD relative to normal weight nonsmokers. SWO are more likely than normal weight smokers to report using cigarettes to manage their weight, to be concerned about gaining weight post-cessation, to have less confidence in their ability to manage their weight without cigarettes, and to resume smoking if they gain too much weight while quitting. This can result in reduced likelihood of attempting to quit and limited success with cessation when a quit attempt is made. Research has suggested that getting smokers who have not been able to quit smoking to switch from combustible cigarettes to electronic cigarettes (EC) could reduce morbidity and mortality. While FDA-approved nicotine replacement therapy (NRT) is another option to facilitate changes in smoking, adherence and acceptability tend to be low. In contrast, EC have been designed to deliver nicotine in bursts that mimics smoking. Behaviorally and pharmacologically, EC may be a better substitute for smoking, leading to higher compliance and helping to prevent cessation-related weight gain. While both NRT and EC may reduce cigarette use in SWO, their efficacy, acceptability, and potential to limit weight gain and improve health has not been compared among SWO. This research project (RP) will randomize 60 SWO to receive (1) EC, (2) NRT, or (3) to a no-product control (CON) condition for 8 weeks. Assessments will occur at baseline, and 1, 2, and 3-months follow-up. In a sample of SWO, aims include: 1) To compare EC, NRT, and CON on smoking, exhaled carbon monoxide, and quit attempts; 2) To compare EC and NRT on acceptability and adherence; 3) To compare EC, NRT, and CON effects on weight, central adiposity, glucose regulation, lipid metabolism, inflammation, and blood pressure at follow-up. Prospective clinical studies are needed to understand whether NRT or EC result in harm reduction by facilitating a switch from cigarettes to an alternate product, reducing cigarette smoking, or by aiding in smoking cessation. This study will be the first to examine the effects of EC and NRT on smoking and health among SWO. These findings add important knowledge about some of the potential effects of EC and NRT use on use of combustible cigarettes and indicators of potential health harm in a population highly vulnerable to smoking-related morbidity and mortality. The CADRE Cores will support the successful completion of the RP and the investigator’s path to research independence. The REACH Core will assist with remote participant recruitment, the CLC Core will provide clinical, technical, and scien...