1. K+ influx and efflux were measured in normal (HbA) and sickle (HbS) red blood cells to investigate the interaction of swelling, H+ ions and urea with O2 (0 to 150 mmHg O2) in the presence of ouabain and bumetanide (both 100 microM). 2. In HbA cells, K+-C1- cotransport was O2 dependent. At low oxygen tensions (PO2s) the transporter was inactive and refractory to low pH, swelling or urea. 3. C1--independent K+ influxes in sickle cells were elevated at low PO2s, as previously reported. C1--dependent K+ influxes were large at both high and low PO2s, whether stimulated by swelling, H+ ions or urea. In the absence of O2, C1--dependent K+ influxes were similar in magnitude to those measured at high PO2s. The minimum for C1--dependent K+ influx was observed at PO2s of about 40-70 mmHg. 4. K+ efflux from HbS cells was stimulated by the addition of urea (500 mM). The rate constants were of similar magnitude whether measured at high PO2 or in the absence of O2, and were predominantly C1- dependent under both conditions. 5. In HbS red blood cells, reduction of extracellular Ca2+, addition of 1 mM Mg2+ or nitrendipine (10 microM) to the saline had no effect. Inhibitors of K+-C1- cotransport, [(dihydroindenyl)oxy] alkanoic acid (DIOA; 100 microM) or calyculin A (0.1 microM), inhibited influxes by a similar magnitude to C1- substitution. 6. Results are significant for the pathophysiology of sickle cell disease. Low pH and urea are able to stimulate KC1 loss from sickle cells, leading to cellular dehydration, even in regions of low PO2.