Studies suggest that reduced-nicotine cigarettes decrease nicotine intake and dependence. However, questions remain about reduced-nicotine cigarette abuse liability, whether reduced-nicotine cigarette exposure lowers reduced- and full-nicotine cigarette use, and whether reduced-nicotine cigarettes substitute for full-nicotine cigarettes. This randomized, double-blind laboratory study used operant behavioral economics to examine abuse liability of cigarettes with varying nicotine content. Non-treatment-seeking smokers (N = 43) self-administered reduced- (5.2, 2.4, or 1.3 mg/g) and full-nicotine (15.8 mg/g) cigarettes before and after 3 weeks of at-home exposure. Participants were randomized to full-nicotine or one of the reduced-nicotine cigarettes to determine the effect of exposure on abuse liability and substitutability. Abuse liability was assessed in single-commodity sessions, and substitutability was measured in concurrent-commodity sessions. In the self-administration sessions, concurrently available reduced-nicotine cigarettes attenuated full-nicotine cigarette demand and rendered reduced-nicotine cigarettes partial substitutes for full-nicotine cigarettes. Exposure to study cigarettes for 3 weeks marginally reduced demand for reduced- and full-nicotine cigarettes irrespective of nicotine content. Results suggest a limited influence of nicotine content on smoking behavior in established smokers and highlight the role of nonpharmacological factors (e.g., taste/smell) on the maintenance of smoking. These results should be considered in determining whether a nicotine-reduction standard is a feasible path for reducing cigarette demand.