The membrane potential of frog skeletal muscle was measured in various solutions, in the presence and in the absence of the CO2/HCO3- buffer. 2. The CO2/HCO3- buffer (PCO2 = 38-593 mm Hg; [HCO3-] = 5-25 mM/1) generally induced a reversible depolarization. 3. In the presence of C1-, there was a slowly developing but marked depolarization. 4. In the absence of C1-, there was an early depolarization which increased in high-PCO2 or low-K+ solutions, and decreased in low-PCO2, high-K+ or Na+-free solutions. Changing the HCO3- concentration did not modify the depolarization. 5. The early depolarization and contractions observed in C1--free Ringer persisted in presence of tubocurarine chloride (2.5-10(-5) M/1). 6. Possible mechanisms for the depolarization are discussed.