The Pediatric Division of the Southwest Oncology Group is attempting to define subgroups of acute lymphoblastic leukemia (ALL) by laboratory delineation of marrow lymphoblast characteristics at diagnosis. Immunological subclassification studies include erythrocyte-forming rosette (E-rosette), C3 receptor, Fc receptor, surface immunoglobulin (Slg) and cytoplasmic immunoglobulin (Clg) determinations, as well as peripheral T (PT), thymocyte, la, and common ALL membrane antigen testing. Four subgroups of ALL have thus far been defined: null (Sig-, Clg-, PT-); pre-B (Slg-, Clg+, PT-); B-cell (Slg+, Clg-, PT-); and T-cell (Sig-, Clg-, PT+). A group of 118 patients have had complete testing, and an additional 121 patients have had partial testing. Thirty five patients with pre-B ALL and 27 patients with T-cell ALL have thus far been studied. Pre-B and null types of ALL appear closely related in multiple subclassification parameters (age, sex, physical findings, white blood cell count, and lymphoblast la and common ALL antigen positivity). Pre-B ALL patients treated with the same treatment regimens as were null ALL patients appear to have shorter durations of complete remission, although the difference has not yet reached statistical significance. Results suggest that the male predominance and older age distribution previously recognized for E-rosette-positive T-cell leukemia can also be expected in the E-rosette-intermediate and E-rosette-negative T-cell ALL subsets, although statistically higher white blood cell counts at diagnosis are seen in the E-rosette-positive subset. Mediastinal mass at diagnosis is most likely in the patient with E-rosette-positive, thymocyte antigen-positive lymphoblasts. The E-rosette-intermediate and E-rosette-negative, as well as the E-rosette-positive, T-cell ALL subsets appear to constitute poor prognosis categories. Correlation with treatment results is preliminary in all groups but suggests that stratification of ALL at diagnosis according to several immunological subgroupings may prove helpful in planning therapy. © 1981, American Association for Cancer Research. All rights reserved.