K+ released from exercising muscle via K+ channels needs to be removed from the interstitium into the blood to maintain high muscle cell membrane potential and allow normal muscle contractility. Uptake by red blood cells has been discussed as one mechanism that would also serve to regulate red blood cell volume, which was found to be constant despite increased plasma osmolality and K+ concentration ([[Formula: see text]]). We evaluated exercise-related changes in [[Formula: see text]], pH, osmolality, mean cellular Hb concentration, cell water, and red blood cell K+ concentration during exhaustive handgrip exercise. Unidirectional86Rb+(K+) uptake by red blood cells was measured in media with elevated extracellular K+, osmolarity, and catecholamines to simulate particularly those exercise-related changes in plasma composition that are known to stimulate K+ uptake. During exercise [[Formula: see text]] increased from 4.4 ± 0.7 to 7.1 ± 0.5 mmol/l plasma water and red blood cell K+ concentration increased from 137.2 ± 6.0 to 144.6 ± 4.6 mmol/l cell water ( P ≤ 0.05), but the intracellular K+-to-mean cellular Hb concentration ratio did not change.86Rb+uptake by red blood cells was increased by ∼20% on stimulation, caused by activation of the Na+-K+pump and Na+-K+-2Cl−cotransport. Results indicate the K+ content of red blood cells did not change as cells passed the exhaustively exercising forearm muscle despite the elevated [[Formula: see text]]. The tendency for an increase in intracellular K+ concentration was due to a slight, although statistically not significant, decrease in red blood cell volume. K+ uptake, although elevated, was too small to move significant amounts of K+ into red blood cells. Our results suggest that red blood cells do not contribute to the removal of K+ released from muscle and do not regulate their volume by K+uptake during exhaustive forearm exercise.