Both halothane (HAL) and acid-base changes produce cardiac arrhythmias in humans. The authors' aim was to determine if HAL alters the effects of hypercapnic acidosis and hypocapnic alkalosis on action potential (AP) properties of ventricular muscle fibers. They superfused the paced right ventricle of 15 guinea pig hearts with non-HCO3buffered salt solution and recorded transmembrane APs with 3 M KCl microelectrodes in 35 subendocardial cells. Random changes in the fractions of HAL were made during low (12% CO2in O2), normal (5% CO2in O2), and high (0% CO2in O2)pH. Compared with controls atpH 7.44, AP duration (APD) and effective refractory period (ERP) significantly decreased by 7 and 4% atpH 8.08 and increased by 7 and 9% atpH 7.09. AtpH 7.44, 0.7–2.1% HAL produced no change in APD; but 2.1% increased ERP, while 3.5% HAL decreased ERP. AtpH 8.08, the decrease in ERP induced with alkalosis alone was converted to an increase with 1.4 and 2.1% HAL. AtpH 7.09, 0.7–1.4% HAL had no additional effect on the acidosis-induced increases in APD and ERP, but 2.1 and 2.8% HAL greatly reduced these responses. At HAL fractions greater than 1.4% the marked inverse changes in APD and ERP, induced alone by acidosis and alkalosis, were no longer significantly different from control. This study shows that the opposing effects of alkalosis to shorten and of acidosis to lengthen APD and ERP were attenuated at low levels and abolished at high levels of HAL. Because increases in ERP may reduce the vulnerability of cardiac fibers to re-entrant excitation, the local proarrhythmogenic effect of alkalosis may be diminished with clinical levels of HAL; also the local antiarrhythmogenic effect of acidosis may be diminished, but only at higher levels of HAL.