1. As it has been suggested that the beneficial effect of methylprednisolone in shock is due to its effect on erythrocyte oxygen affinity, we studied its effect on incubated erythrocytes and on haemoglobin solution. 2. Incubation of fresh whole blood anticoagulated with acid/citrate/dextrose with methylprednisolone (7 mmol/l) produced a significant decrease in oxygen affinity, which was not seen with lower concentrations of methylprednisolone. When either acid/citrate/dextrose blood stored for 10 days or fresh heparinized blood was used, no significant increase in the partial pressure of oxygen at 50% haemoglobin saturation ( P 50 ) was demonstrated even with methylprednisolone at 7 mmol/l. At the highest concentration achieved in plasma with standard therapeutic doses (56 μmol/l) there was no increase in P 50 under all the conditions studied. 3. Methylprednisolone reduced the oxygen affinity of haemoglobin in solution. The reduction in oxygen affinity was less than that produced by 2,3-diphosphoglycerate and more than that of either sodium succinate or sodium chloride. 4. From the results of this study we conclude that the effect observed in whole cells is probably due to a direct effect of methylprednisolone on haemoglobin. To produce a significant decrease of oxygen affinity of whole blood in vitro requires a plasma concentration of methylprednisolone above that obtained in plasma in vivo , with the currently used therapeutic doses.