A longitudinal study of the red blood cell (RBC) deformability, percent of dense erythrocytes, and hematologic parameters has been conducted during 117 painful crises affecting 36 patients with sickle cell anemia between January, 1985 and December, 1990. RBC deformability was determined by osmotic gradient ektacytometry and the percentage of dense cells was quantitated by centrifugation on a discontinuous Stractan density gradient. The data indicate that the painful crisis is a process that follows a bimodal form of evolution. The first phase of the painful crisis is characterized by increase in the severity of pain, increase in the number of dense cells, and a decrease in RBC deformability. In some patients the changes in dense cells and RBC deformability are evident 1 to 3 days before the onset of pain. In addition, the hemoglobin level decreases and the reticulocyte count increases during this initial phase. The second phase of the crisis is characterized by reduction in pain intensity, decrease in the number of dense cells, and increase in RBC deformability to values higher than those seen in the steady state. Moreover, the improvement in RBC deformability and the decrease in the number of dense cells at the end of a crisis seem to constitute new risk factors that may incite a recurrence of the crisis within 1 month in about 50% of painful episodes. The pathophysiologic events responsible for this bimodal behavior of RBCs during painful episodes may represent the appearance of factors that induce (1) preferential trapping of deformable cells in the microcirculation during the first phase of the crisis, followed by a decrease of dense cells and the appearance of new deformable RBCs released from the bone marrow during the second phase of the crisis; or (2) variable sickling of all circulating RBCs during the first phase followed by disappearance of dense RBCs and their replenishment by deformable cells during the second phase.