We reported previously that painful crises in patients with sickle cell anemia are accompanied by striking decreases in the percent of densest red cells (fraction 4) when studied with isopyknic Percoll-Stractan gradients. We report that an alternative to density gradients is the red cell distribution width (RDW), an estimate of red cell size variation measured with a Coulter counter. In 17 painful crises in 12 patients with homozygous sickle cell anemia the RDWs decreased in each crisis, from an initial mean of 16.2 +/- 1.8 SD to 12.8 +/- 1.3 (P less than 0.001). In patients in whom serial measurements of both RDW and fraction 4 (very dense) red cells were taken during crisis, the two measurements declined in parallel. The decrease of RDW is a readily observable and objective laboratory concomitant of painful sickle crisis.