Background Prospective studies consistently find that smoking is a risk factor for the development of panic disorder (PD). A possible explanation is that nicotine deprivation promotes heightened sensitivity to bodily sensations and/or arterial carbon dioxide (CO2). Abrams et al. (2011) previously found that, in response to a CO2 rebreathing challenge, smokers experiencing more (vs. less) intense nicotine withdrawal had more severe panic symptoms and a stronger urge to escape. However, participants were aware of the last time they smoked, leaving unclear the extent to which fear reactivity was influenced by the pharmacologic effects of nicotine deprivation versus beliefs regarding when nicotine was most recently used. The present study aimed to ascertain whether nicotine deprivation, independent of beliefs regarding recent nicotine use, promotes fear reactivity among smokers. Methods Moderate to heavy smokers without PD (N = 25) participated in a placebo‐controlled, double‐blind study consisting of two sessions spaced 1 week apart. Participants abstained from nicotine for 2 hr prior to sessions. During one session participants were given a 21 mg nicotine replacement patch and, during the other, a placebo patch, with the order counterbalanced. For both sessions, after a 3‐hr absorption period, participants underwent a 10‐min CO2 rebreathing challenge. Results Wearing a nicotine (vs. placebo) patch increased self‐reported panic reactivity among participants, but did not significantly affect physiological and behavioral measures of reactivity. Conclusions In smokers without a history of PD, nicotine deprivation attenuates subjective panic reactivity. Possible explanations for the contrast between theory and laboratory findings as well as clinical implications are discussed.