Irreversibly sickled cells (ISC) are considered to be a hallmark of sickle cell disease, yet their number in peripheral blood smears varies greatly among different homozygous SS patients. This variation has suggested a role for ISC in the varying clinical manifestations of the disease. Efforts to determine the role of ISC have been complicated by the difficulty in standardizing the quantification of these cells. For this reason, we have attempted to develop an alternative method of quantification that would be less variable than the microscopic counting of cells on blood smears. Because ISC are dehydrated dense cells, a measurement based on cell density seemed an attractive alternative approach. Analysis of whole blood samples on a simple, 2- step density gradient, spun in a microhematocrit centrifuge, showed a strong correlation between the proportion of high density cells and the percentage of morphologically identified ISC. Parallel ektacytometric measurements of cell deformability, another parameter that reflects the low water content and high MCHC of ISC, were also strongly correlated with ISC counts. These findings suggest that either of these measurements, sensitive to the special physical properties of ISC, could be used as an objective substitute for the microscopic counting of ISC.