Summary. KCl cotransporter activity in sickle (HbSS) red blood cells (RBCs) was measured in cells suspended in 'simple' physiological saline, saline augmented with inorganic salts, and autologous plasma. Our results showed that the transporter was only functioning at 20% of the level of cells in saline when cells were resuspended in autologous plasma. Kinetic analysis of the data showed that plasma decreased both V max and K m for K + of the transporter. The plasma factor(s) responsible was heat-stable and dialysable (i.e. size < 10 kD).Adding magnesium, calcium, inorganic phosphate or bicarbonate to 'simple' saline to mimic the effect of plasma revealed that Mg 2+ and Ca 2+ had no significant effect at physiological concentrations. P i was not effective at 1 . 1 mM , but did inhibit significantly (42Ϯ2%Þ at 5 . 6 mM . HCO ¹ 3 had a major inhibitory effect on K + influx when added to saline, and was identified as the principal candidate for the plasma effect.We suggest bicarbonate may play a significant role in modifying KCl cotransport, and hence HbSS cell volume in vivo. It acts by altering the set point of the transporter via the signalling systems involved in its regulation.