["Addiction, Volume 121, Issue 7, Page 1888-1898, July 2026. ", "\nAbstract\n\nBackground and aims\nBy assessing neuroaffective response to motivationally relevant cues before a quit attempt, we have shown that smokers who attribute greater incentive salience to cigarette‐related cues than non‐cigarette‐related rewards (Sign‐trackers, ST) benefit more from varenicline compared with smokers with the opposite neuroaffective reactivity profile (Goal‐trackers, GT). This proof‐of‐concept trial aimed to extend this work by testing whether the efficacy of varenicline relative to nicotine replacement treatment differs across the two neuroaffective reactivity profiles.\n\n\nDesign\nA 2‐group, double‐blind, randomized controlled clinical trial with stratification on ST versus GT classification (based on baseline‐assessed neuroaffective reactivity profiles) for adults seeking to quit smoking using varenicline or nicotine replacement therapy (NRT).\n\n\nSetting\nHospital‐based outpatient clinic specializing in smoking cessation treatment, located in Houston, Texas, USA.\n\n\nParticipants\n158 community volunteers (78 randomized to varenicline and 80 to NRT): 18–75 years of age, smoking 5 or more cigarettes/day and without severe comorbid psychiatric disorders, uncontrolled medical illnesses or contraindications for pharmacotherapy.\n\n\nInterventions and comparators\nTwelve weeks of varenicline or NRT combined with brief cessation counseling.\n\n\nMeasurements\nPrimary outcome: continuous smoking abstinence over the last 4 weeks of treatment. Secondary outcomes: continuous abstinence at 3‐ and 6‐month follow‐ups.\n\n\nFindings\nUsing a Bayesian approach, we estimated the probability that an interaction between treatment and neuroaffective profile exists. We pre‐specified a probability above 80% as evidence for an interaction. Logistic regression indicated a 92.7% probability that an interaction between treatment and neuroaffective profile exists, exceeding the pre‐specified threshold. Individuals with the ST profile responded better to varenicline than to NRT. At the end of treatment, the ST group showed a 35% Absolute Risk Difference (ARD) favoring varenicline over NRT (absolute cessation rates: 47% and 11%, respectively). In contrast, among individuals with the GT profile, the benefit of varenicline was smaller, with an ARD of 13% (absolute cessation rates of 29% for varenicline and 17% for NRT). The varenicline advantage for the ST group persisted at 3‐ and 6‐month follow‐ups.\n\n\nConclusions\nSmokers seeking to quit who attribute greater incentive salience to cigarette‐related cues than non‐cigarette‐related rewards benefit more from varenicline than from nicotine replacement therapy. These findings support using neuroaffective biomarkers to inform personalized smoking cessation interventions.\n\n"]