Preliminary data suggest that cotinine, the major metabolite of nicotine, may be behaviorally active. Studies involving the administration of cotinine at doses that produce high blood concentrations (in excess of those produced by cigarette smoking) may be of interest. This inpatient, 10-day human study examined the safety and the effects from several high doses of oral cotinine fumarate (40, 80, or 160 mg) or placebo in abstinent cigarette smokers. All subjects smoked cigarettes ad lib during the first 2 days of the study, then were required to be abstinent beginning on the third day. All subjects were given placebo on this day to wash out nicotine before the administration of cotinine. Subjects were subsequently randomly assigned in a double-blind manner to cotinine or placebo for the next 3 days to determine the safety profile of cotinine. All subjects were given placebo on the final 3 days to examine cotinine withdrawal symptoms. The results showed no significant physiologic, subjective, or performance effects across the various doses of cotinine and placebo. Furthermore, no cotinine withdrawal effects were observed. This study demonstrates that short-term administration of cotinine to humans at levels as high as 10 times that attained from cigarette smoking is safe with no observable acute or withdrawal effects from cotinine in this setting.