The antisickling effects of eight thiol reagents that cross the red cell membrane and then react with the cysteine/393, the only accessible thiol group of hemoglobin, have been investigated at various P02 values. In spite of completely reacted hemoglobins, the potent antisickling effect varied from one compound to the other and was partially related to the extent of the increased oxygen affinity of intact sickle cells induced by these compounds. The formation of methemoglobin upon the incubation of red blood cells with some disulfides had only a small effect on the sickling process.