This study characterized the effects of caffeine (1.0-30.0 mg/kg) and nicotine (0.1-3.0 mg/kg) administered alone and in combination on ventilation in unanesthetized rhesus monkeys. In seated monkeys prepared with a head plethysmograph, ventilation was measured during exposure to air (normocapnia), CO2 (3%, 4% and 5%) mixed in air (hypercapnia), 10% O2 mixed in N2 (hypoxia) and 100% O2 (hyperoxia). Caffeine produced marked, dose-dependent increases in ventilation during conditions of normocapnia and hypercapnia. In contrast, acute administration of nicotine had less pronounced respiratory-stimulant effects during all conditions. The joint effects of caffeine and nicotine on ventilation generally did not differ from those obtained with caffeine alone. Chronic administration of nicotine (1.0 mg/kg/day) for 4 consecutive wk via osmotic pumps significantly decreased the half-life of caffeine but had little effect on ventilation or on sensitivity to the respiratory-stimulant effects of caffeine. Two primary metabolites of caffeine, theophylline and paraxanthine, were active as respiratory stimulants and were equipotent to caffeine, and the joint effects of caffeine and its metabolites were additive. The results indicate that caffeine and nicotine stimulate respiration through different pharmacological mechanisms, in contrast to caffeine and its metabolites which exhibit a similar pharmacological profile. Moreover, significant pharmacokinetic interactions may be obtained when caffeine and nicotine are coadministered.