Pain detection threshold (latency in seconds) was repeatedly assessed by a standardized, computer-controlled radiant heat stimulus applied to the skin before and after nicotine intake in 3 studies of smokers and nonsmokers. Placebo or doses of nicotine corrected for body weight were administered by measured-dose nasal spray. Nicotine increased pain latency (i.e., decreased pain sensitivity) significantly in each study, although effects were modest and somewhat inconsistent. Nicotine had no effect on skin temperature at the site of stimulation, arguing against an indirect effect on nociception through peripheral cardiovascular changes. Overall, there were no significant differences as a result of smoking status, indicating that nicotine's influence on pain sensitivity is a “true” drug effect and is not due to withdrawal relief. These findings suggest that nicotine produces an antinociceptive effect in humans, but its relationship to nicotine reinforcement is unclear.