The etiopathologic basis of painful crisis in sickle cell anemia is largely unknown, and no objective criteria for its diagnosis and follow-up exist at present. We have studied 11 patients through 14 painful crises and observed a significant decrease of the densest fraction of red cells in 12 of the 14 crises as determined by isopycnic Percoll-Stractan continuous density gradients. If the first observation is normalized to 100%, the average decrease in dense cells was 77% with a range of 36% to 94%. The time needed for the percentage of dense cells to return to the steady-state level varied from seven to more than 30 days. These findings were in sharp contrast to the stability of the density pattern observed in another group of sickle cell patients, who were studied during crisis-free periods. The mechanism of the disappearance of dense cells could involve selective destruction by the reticuloendothelial (RE) system, selective sequestration in the areas of vasoocclusion, or a combination of both factors.