Summary. The effects of hydrostatic pressures up to 62 MPa upon the voltage-clamp currents of intact squid giant axons were measured using mineral oil as the pressure transmitting medium. The membrane resistance and capacitance were not appreciably affected over the whole range of pressures explored. The predominant effect of pressure is to slow the overall kinetics of the voltage-clamp currents 9 Both the early (Na) currents and the delayed (K) ones were slowed down by approximately the same time scale factor, which was in the range of 2 to 3 when pressure was increased from atmospheric to 62 MPa.Finer details of the effects, most evident at moderate depolarizations, are: the apparent initial delay in the turn-on of Na currents is increased by pressure less than is the phase of steepest time variation, and the later decay is slowed more than is the rising phase. The initial time course of the currents at high pressures can be made to overlap with that at normal pressure by a constant time compression factor, Ore, together with a small, voltage-dependent delay 9In a given axon, Om was fairly independent of voltage, and it increased exponentially with pressure according to an apparent activation volume, A V • ranging between 32 and 40 cmJ/mole. A V • tended to decrease with increasing temperature. Contrary to what is observed for moderate or large depolarizations, the kinetics of Na inactivation produced by conditioning prepulses of -50 or -60 mV was little affected over the whole range of pressures explored.Inferences about the pressure dependence of the steady-state Na activation were made from the comparison of the plots of early peak currents, Ip, versus membrane potential, E. The Na reversal potential, ENd, and the slope of the plots near EN, did not change significantly with pressure, but the peak Na conductance vs. E relationship was shifted by about + 9 mV upon increasing pressure to 62 MPa. Steady-state Na inactivation, h| was slightly affected by pressure. At 62 MPa the midpoint potential of the h~(E) curve, Eh, was shifted negatively by about 4 mV, while the slope at Eh decreased by about 38%.Under the tentative assumption that pressure directly affects the gating of Na channels, the Na activation data follows a simple Hodgkin-Huxley scheme if the opening of an m gate involves an activation volume of about 58 A_ 3 and a net volume increase of about 26 A 3. However, a self-consistent description of the totality of the effects of pressure on Na inactivation cannot be obtained within a similar simple context.