The small electrical resistance in series with the axon membrane is generally modeled as the intercellular pathway for current flow through the periaxonal glial (Schwann cell) sheath. The series resistance of the medial giant axon of the crayfish, Procambarus clarkii, was found to vary with conditions known to affect the electrical properties of the periaxonal glia. Series resistance was estimated from computer analysed voltage waveforms generated by axial wire-constant current and space clamp techniques. The average series resistance for all axons was6.2 ± 0.5 Ωcm 2 ( n = 128). Values ranged between 1 and 30 Ωcm 2. The series resistance of axons with low resting membrane resistance (< 1500 Ωcm 2) increased an average of 30% when stimulated for 45 s to 7 min (50 Hz) whereas the series resistance of high membrane resistance (> 1500 Ωcm 2) axons decreased an average of 10%. Carbachol (10 −7 M) caused the series resistance of low membrane resistance axons to decrease during stimulation but had no effect on high membrane resistance axons. d-Tubocurare (10 −8 M) caused the series resistance of high membrane resistance axons to increase during stimulation but had no effect on low membrane resistance axons. Bumetanide, a Na-K-Cl cotransport inhibitor and low [ K +] o, prevented the stimulation-induced increase in series resistance of low membrane resistance axons but had no effect on the high membrane resistance axons. The results suggest that the series resistance of axons varies in response to the activity of the glial K + uptake mechanisms stimulated by the appearance of K + in the periaxonal space during action potential generation. An increase or decrease in the series resistance is a function of which K + uptake system (bumetanide-sensitive or ouabain-sensitive) dominates. Which system dominates depends on the quantity of periaxonal K + and the action of the glial cell cholinergic system on the electrochemical gradient for K +.