Lymphoblasts from 93 children with acute lymphoblastic leukemia (ALL) were characterized by immunologic cell surface markers. These patients were treated on a single protocol, featuring adriamycin therapy during remission, and have been followed from 2 to 6.5 yr (median 4 yr). Three classes of patients were defined serologically: HTA+ Ia- CALLA-, Ia+ CALLA+ HTA-, and Ia+ CALLA- HTA-. Disease-free survival and sites of relapse were assessed within immunologic subsets. Similar to the findings of others, T-cell (HTA+ Ia-) patients fared poorly as compared to non-T-cell (Ia+ HTA-) patients (median disease-free survival was 12 and 47 mo. respectively; p = 0.0004). The majority of relapses in the HTA+ patients occurred at extramedullary sites. Late testicular relapse was rare among Ia+ patients. In addition, the “common ALL antigen” (CALLA) may identify a relatively favorable subset within the Ia+ population. The prognostic value of the immunologic markers was compared with traditional clinical factors. There was much overlap between HTA+, older age, and elevated WBC. However, neither age nor WBC alone were of prognostic significance among the Ia+ patients. We conclude that surface markers define both biologic and prognostic characteristics. The course of childhood ALL must be viewed in the context of homogeneous subsets and within particular therapeutic programs.