Differential interference contrast (DIC) microscopy (Nomarsky optics) readily demonstrates the formation of “pits” or crater-like depressions in red cell membranes of splenectomized individuals. Splenic reticuloendothelial dysfunction characteristic of many patients with sickle cell disease (SCD) can be demonstrated by technetium spleen scans, but this technique is expensive, requires injection of radioactive material into children, and is cumbersome to perform at regular intervals. However, pit formation in red cells, which also appears to reflect splenic dysfunction, can readily be quantitated in a finger-stick blood sample using DIC microscopy. In this study, the degree of red cell pitting was compared with results of technetium spleen scans and measurements of Howell-Jolly bodies in individuals with sickle cell disease. The average pitted cell percentage in the control population was 0.5% +/- 0.5 (range 0.0–2.6) and 30.5% +/- 13.9 in the SCD population (range 2.4-71.1) (less than 0.001). Of the individuals studied with SCD, 12 also had technetium (99mTc) sulfur colloid scans and measurements of Howell-Jolly bodies. The percentage of Howell-Jolly bodies was low and did not correlate well with the degree of splenic visualization. However, there was an excellent correlation between pit count and splenic dysfunction as measured by spleen scan. Determination of red cell pitting, therefore, appears to offer a simple means for clinical evaluation of splenic reticuloendothelial function in patients with SCD.