This study investigated the effect of acute deoxygenation on membrane permeability characteristics of sickle cells. Measured fluxes of Na+ and K+ in ouabain-inhibited cells, of chloride and sulfate exchange in 4,4′-diisothiocyanostilbene-2,2′-disulfonate (DIDS)-inhibited and untreated cells, and of erythritol, mannitol, and arabinose in cytochalasin B-inhibited cells indicated that a deoxygenation-induced permeability change occurred in sickle cells only for cations and chloride. Monovalent cation permeabilities increased five-fold, and chloride influx into DIDS treated cells was enhanced nearly threefold on sickle cell deoxygenation. In contrast, no detectable increase in permeability to the other solutes was found. To gain perspective on these findings, similar measurements were performed in normal cells treated with diamide, an agent shown by others to induce a coupled increase in membrane permeability and phospholipid translocation, reminiscent of deoxygenation-induced changes in sickle cells. Although the increase in cation permeability was no greater than that in sickled cells, treatment with 2 mmol/L diamide also produced a twofold increase in the first order rate constants for sulfate exchange and mannitol efflux, indicating a relatively nonselective permeability increase that permitted flux of larger solutes than in the case of deoxygenated sickle cells. These results suggest that the deoxygenation of sickle cells induces a permeability increase that is relatively insensitive to charge, but is restrictive with respect to solute size.