We investigated the effect of caffeine on the hypercapnic ventilatory response (HCVR) using steady state (SS) and rebreathing (RB) methods in 6 subjects. They received caffeine (5 mg/kg) or saline intravenously in a randomized, double-blind, crossover manner, with measurement of serum caffeine levels. PETCO2 and (VE), normalized for vital capacity (VC), were measured continually during RB and during the last 5 min of SS runs. The slope of the VE-PETCO2 response increased from 0.21 +/- 0.14 to 0.38 +/- 0.14 and from 0.23 +/- 0.12 to 0.59 +/- 0.45 VC.min-1.mmHg-1, measured by RB and SS respectively (P < 0.05). Plotting VT vs PETCO2 revealed a parallel shift (additive effect) in the response measured by RB after caffeine; but an increased slope (multiplicative effect) in the VT-PETCO2 relation measured in SS. We conclude that caffeine acts as a respiratory stimulant and increases the HCVR, but that assessment of the caffeine-CO2 interaction is dependent on the methodology employed.