The aim of this study was to determine the analgesic effect of acetaminophen compared to a combination of both caffeine and acetaminophen or caffeine alone using tonic and phasic pain stimulation. Twenty-four subjects were treated orally with 1000 mg acetaminophen, 130 mg caffeine, and a combination of both in a 4-way crossover, double-blind, placebo-controlled study. Pharmacokinetics and analgesic effects were assessed by means of an experimental pain model based on pain-related cortical potentials after phasic stimulation of the nasal mucosa with CO(2) and based on pain ratings after tonic stimulation with dry air. Analgesic effects of acetaminophen and acetaminophen plus caffeine but not caffeine alone caused a significant reduction of pain-related cortical potentials beginning 30 minutes after medication. The combination demonstrated an enhanced effect throughout the observation time up to 3 hours. Caffeine accelerated acetaminophen absorption, indicated by enhanced early AUCs. Significant analgesic effects of the combination on tonic pain ratings were found throughout the observation time as compared to acetaminophen and placebo. In this study, caffeine enhanced and prolonged the analgesic activity of acetaminophen.