We have investigated the mechanisms involved in sickle cell dehydration upon continuous or cyclic deoxygenation: the Ca(2+)-activated K+ channel and the KCl co-transport system. Short-term continuous deoxygenation (1 h) of sickle cells in a Ca(2+)-containing medium promoted a stimulation of the efflux of K+ and cell dehydration. This latter was reduced by the replacement of Ca2+ in the medium by EGTA, but not by addition of [(dihydro-indenyl) oxy] alkanoic acid (DIOA), an inhibitor of the KCl co-transport. During cycles of deoxygenation-reoxygenation, cell dehydration was partly prevented by EGTA and significantly reduced by DIOA only in the presence of Ca2+. The present data support the view that sickle cell dehydration during deoxygenation arises from the stimulation of the Ca(2+)-dependent K+ permeability leading to water loss, whereas during reoxygenation periods, subsequent activation of the KCl co-transport also contributes to cell dehydration.