PROJECT SUMMARY/ABSTRACT Current tobacco treatment is limited by physicians infrequently prescribing cessation medication (<20%), patients infrequently using cessation medication (~33%), and limited medication effectiveness (<30%). A multilevel intervention to personalize tobacco treatment, based on substantial data linking genetically informed markers to treatment response, has the potential to address these critical gaps by addressing multiple targets in the cascade of treatment success. First, precision treatment may increase treatment effectiveness by matching the smoker with the medication that maximizes efficacy and safety. Second, it may increase physicians’ likelihood of prescribing because they expect precision treatment to be more effective than standard treatment. Third, precision medicine may increase patients’ motivation to initiate and adhere to cessation medication, as evidence suggests that smokers express desire for gene-guided treatment and increased motivation to use it adherently. Emerging evidence including a recent Cochrane review and our research suggests that patients’ ability to quit smoking and respond to cessation medication are associated with multiple biomarkers involved in nicotine metabolism (i.e., nicotine metabolite ratio, NMR) and nicotinic receptor function (i.e., genotype of CHRNA5 variant rs16969968). Evaluating precision treatment based on multiple markers in a multilevel intervention using behavior change theories will advance the field of tobacco treatment. Our preliminary work demonstrated: 1) promise of using both genetic and metabolic markers in guiding treatment, 2) high interest in gene-guided treatment and its potential for enhancing medication use among smokers, 3) higher motivation for smoking cessation with use of genetic risk communication feedback tools, and 4) successful use of health informatics to implement a multilevel tobacco intervention in clinic settings. The proposed study aims to test a multilevel intervention precision treatment intervention using both genetic and metabolic markers, directed at physicians and patients, to increase the uptake and effectiveness of tobacco treatment in primary care. We propose a 2-arm cluster randomized controlled trial of 40 physicians and 800 patients who smoke randomized to usual care (UC) vs. precision treatment (PT) based on NMR and genetics in primary care. We hypothesize that PT will enhance cessation success via increased physician prescription of medication, patient adherence, and treatment effectiveness. In Aims 1 and 2, we will test the impact of PT on physician prescribing, patient use of medication, and patient smoking abstinence. In Aim 3, we will evaluate mechanisms of behavior change and implementation outcomes. The study reflects a significant and innovative paradigm shift from a traditional treatment model to precision treatment that includes both metabolic and genetic markers to motivate and guide tobacco treatment for both physicians a...