Red blood cells (RBC) and reticulocyte parameters were determined on peripheral blood from a subset of patients enrolled in the multicenter study of hydroxyuea (HU) in sickle cell anemia. Multiple blood samples were obtained every 2 weeks. Cellular indices were measured by flow cytometry. Generalized linear models were used to determine the relationship between the longitudinal trajectories of RBC and reticulocyte indices and HU usage. There was a significant relationship between HU usage and most of the RBC and reticulocyte indices. Hydroxyurea produced higher value trajectories than those generated by placebo usage for the hemoglobin (Hb) content of both the RBCs and reticulocytes and for the mean corpuscular volume (MCV) of reticulocytes. These changes were first detected 10 weeks after starting HU and before the increase in Hb F levels. The data suggest that subtle and early markers of response to HU reside in the hemogram.