Thirty children with previously untreated acute lymphoblastic leukemia were studied prior to therapy to determine whether sheep erythrocyte (E)-receptor status correlated with clinical factors, cytochemical staining characteristics, FAB morphologic classification, and karyotype. Five patients (17%) with more than 50% E+ blasts had intense focal acid phosphatase staining and distinct clinical characteristics, including high leukocyte counts, mediastinal masses, and involvement of the central nervous system at diagnosis. Focal acid phosphatase activity was present in blasts of patients with greater than 20% E+ blasts, but this group had fewer poor risk factors. Morphologic and karyotypic features were not related to erythrocyte-receptor status, but the L2 morphologic appearance occurred more frequently in older patients (P less than 0.05). Erythrocyte receptors have both qualitative and quantitative clinical correlations in childhood acute lymphoblastic leukemia; however, E+ and E- groups are heterogeneous and E+ groups must be analyzed for other risk factors and relapse rates determined before firm conclusions can be made about erythrocyte rosetting as an independent risk variable.