BackgroundNicotine replacement therapy (NRT) is an effective treatment but is associated with poor adherence during smoking cessation attempts. This study aimed to determine if In Vivo Sampling, an experiential intervention that includes sampling of NRT in-session, increases NRT adherence and smoking abstinence compared to standard smoking cessation behavioral counseling. MethodsEligible participants were under community corrections supervision and smoked five or more cigarettes per day for the past year. Participants were randomly assigned to receive either In Vivo Sampling or standard smoking cessation behavioral counseling. Both interventions involved four 30-minute sessions and received 12 weeks of combination NRT. Self-reported NRT adherence, quit attempts, and carbon monoxide (CO)-verified smoking cessation were measured at one, three-, and six-months post-intervention. ResultsFrom 2017 to 2022, 515 participants were enrolled and randomized. The In Vivo Sampling group had significantly greater mean adherence to patch and lozenge NRT regimens (71% vs. 60%, OR: 1.63, 95% CI: 1.36-1.96, p<.001). The In Vivo group had a significantly higher likelihood of quit attempts across time (61% vs. 53%, OR: 1.4, 95% CI: 1.05-1.87, p=.021). Groups did not significantly differ on the percent of participants who had quit smoking at 6 months post-intervention (17% In Vivo Sampling vs. 13% standard counseling, OR: 1.43, p=.24). ConclusionIn Vivo Sampling demonstrated better NRT adherence and quit attempts but similar cessation rates to standard behavioral counseling. The In Vivo Sampling intervention represents a novel approach that increased behaviors typically associated with successful cessation over standard behavioral counseling.