Introduction This study assessed the impact of expectancy and administration components of acute nicotine inhaler use on craving, heart rate, and smoking behavior in smokers with varying intentions to quit. Methods 47 dependent smokers that differed in self-reported intention to quit (no intention to quit during the next month N = 26 vs. intention to initiate a quit attempt within 2 weeks N = 21) were randomly administered a 4 mg nicotine or nicotine-free inhaler across two sessions. Instructions regarding the inhaler's nicotine content (expect nicotine vs. expect nicotine-free; nicotine expectancy) and flavor (mint vs. citrus) varied across sessions. Craving and heart rate were assessed before and after inhaler administration (two-second inhalations every 10 seconds over 20 minutes). Next, participants were offered an opportunity to self-administer puffs of their preferred tobacco brand during an hour-long progressive ratio task. Results Across participants, nicotine expectancy independently reduced withdrawal related craving (p = .018), but no comparable effects of nicotine administration were evident. In quitting motivated smokers, nicotine expectancy and administration interacted to reduce intention to smoke (p = .040), while nicotine expectancy (p = .047) and administration (p = .025) independently reduced intention to smoke in quitting unmotivated smokers. Blunted heart rate reactivity to nicotine administration was observed in quitting motivated relative to unmotivated smokers (p = .042); however, neither expectancy nor administration impacted smoking behavior in either group (p values > .25). Conclusions Findings indicate that participant quitting intentions moderate acute nicotine replacement therapy responses. In quitting motivated smokers, a combination of pharmacological and psychological factors may be necessary for nicotine replacement therapy to impact craving. Implications Findings from this study demonstrate that motivations to quit smoking moderate subjective and physiological responses to acute nicotine administration and expectancy in dependent cigarette smokers. Quitting motivated smokers showed blunted heart rate reactivity to nicotine administration, suggesting that they may be less sensitive to the rewarding aspects of nicotine consumption. Nicotine administration and expectancy were found to interact to reduce craving in quitting motivated but not in unmotivated smokers, suggesting that pharmacological and psychological factors may be necessary for nicotine replacement therapy to impact craving in smokers who plan to quit.