Nicotine polacrilex gum is widely used as substitution therapy during cigarette smoking cessation. We studied circadian blood nicotine concentrations, daily intake of nicotine, and extraction of nicotine from gum in smokers switched experimentally to 2 or 4 mg nicotine gum, 12 pieces per day. Nicotine levels and intake were much lower while chewing gum than during ad libitum smoking. Extraction of nicotine from gum by the chewer was incomplete, averaging 53% and 72% for 2 and 4 mg gum, and variable (more than twofold) among individuals. The systemic dose of nicotine was less than expected based on analysis of nicotine in the chewed gum. Disproportionately higher metabolite-to-nicotine ratios while chewing gum compared with smoking suggested that some nicotine was swallowed and underwent first-pass metabolism. Nicotine and metabolite data were used to estimate buccal vs. gastrointestinal absorption. Relative buccal absorption vs. swallowing of nicotine appears to be an important determinant of systemic nicotine intake.