The penetration of (14)C-labeled erythritol, mannitol, and sucrose through the axolemma was determined in medium sized paired axons, one at rest and the other stimulated 25 times per sec. The resting permeabilities, in 10(-7) cm/sec, are erythritol, 2.9 +/- 0.3 (mean +/- SEM); mannitol, 2.3 +/- 0.4; and sucrose 0.9 +/- 0.1. In the stimulated axons they are: erythritol, 5.2 +/- 0.3; mannitol, 4.0 +/- 0.5; and sucrose, 1.8 +/- 0.3. Thus, the calculated permeabilities during activity (1 msec per impulse), in the same units, are: 100, 75, and 38, respectively. These changes in permeability are reversible. The effects of external potassium and sodium concentrations on erythritol penetration were also studied. At rest, erythritol penetration is independent of potassium and sodium concentrations. In the stimulated axons, erythritol penetration decreases when the extracellular sodium is diminished. Sodium influx (not the efflux) decreases during rest and activity when the extracellular sodium is diminished. The diminution during activity of erythritol and sodium entries in low sodium solutions may be related to a decrease of a drag effect of sodium ions on the nonelectrolyte molecules or to independent effects of the sodium concentration on sodium influx and the nonelectrolyte pathways. The axolemma discriminates among erythritol, mannitol, sucrose, and the different ionic species during rest and activity.