Project Summary Tobacco use is the leading preventable cause of both premature deaths overall and cancer deaths in the US. Most smokers visit a healthcare setting each year, providing an unequaled opportunity to intervene. Yet, most smokers do not receive highly effective cessation treatment during their healthcare visits. To improve the effectiveness of smoking treatment in healthcare, this project will identify especially promising medication regimens and counseling modalities for use in primary care for the two most effective smoking cessation pharmacotherapies: varenicline and combination nicotine replacement therapy (C-NRT). The criteria for identifying promising varenicline and C-NRT treatments will include 1-year biochemically confirmed point- prevalence abstinence and cost. Smokers (N=608) from primary care clinics, who want to quit smoking, will be randomized to receive one of two levels of each of four factors: 1) Medication Type (Varenicline vs. C-NRT), 2) Preparation Medication (4 weeks vs. Standard), 3) Medication Duration (Extended [24 weeks] vs. Standard [12 weeks]), and 4) Counseling Modality (In-Person vs. Phone). The proposed research builds on our expertise and prior research findings to address a critical knowledge gap: i.e., how best to use the most effective smoking cessation pharmacotherapies in real-world healthcare settings. This research will use an efficient and innovative methodology (i.e., the Multiphase Optimization Strategy) to identify the most promising C-NRT and varenicline-based treatments to use with primary care patients who smoke. These especially promising (“optimized”) treatments will then be evaluated in a randomized clinical trial in the Optimized Care Project of this Program Project.