The effects of the acute administration of nicotine [through nicotine inhalers (NI) and placebo inhalers (PI)], nicotine-containing tobacco (NT), and denicotinized tobacco (DT), on smokers' subjective responses and motivation to smoke were examined in 22 smokers (12 male, 10 female; 11 low dependent, 11 high dependent). During four randomized blinded sessions, participants self-administered NI, PI, NT, or DT, and assessed their effects using Visual Analogue Scales and the Brief Questionnaire of Smoking Urges. They could then self-administer their preferred brand of cigarettes using a progressive ratio task. NT and DT were each associated with increased satisfaction and relaxation as well as decreased craving relative to the inhalers and NT increased ratings of stimulation relative to each of the other products. Both NT and DT delayed the onset of preferred tobacco self-administration relative to NI and PI but only NT reduced the total amount self-administered. Sex differences were evident in the effects of DT on withdrawal-related cravings with women experiencing greater DT-induced craving relief than men. Findings suggest that DT is effective in acutely reducing many smoking abstinence symptoms, especially in women, but a combination of nicotine and non-nicotine tobacco ingredients may be necessary to suppress smoking behavior.