Nicotine is the primary psychoactive constituent of tobacco smoke, but it is not clear whether the reinforcing effects of cigarette smoking can be attributed solely to nicotine intake. In this study, two groups of male and female smokers participated in three sessions involving intermittent exposure to moderate low, or no nicotine doses via controlled tobacco smoking ("smoke," n = 20) or measured-dose nasal spray ("spray," n = 16). Visual analog scales of subjective effects (VAS) and heart rate (HR) were obtained within 5 min of each dosing. Plasma nicotine levels indicated comparable dosing between methods. For both methods, there were significant nicotine dose effects for most subjective measures and HR. More importantly, the pattern of effects across doses was virtually identical between methods, as nicotine intake via smoking or spray significantly increased HR and the VAS scales of Head Rush and Dizzy, decreased Hunger and Desire to Smoke, and had no effect on Comfortable, Jittery, or Relaxed. These results suggest that rapid nicotine uptake by novel methods may provide effects very similar to nicotine intake by smoking.