Early detection of relapse in children with acute lymphoblastic leukemia (ALL), as well as distinction of leukemic blasts from hematogones, can be difficult by morphologic examination alone. Using CD34 and terminal deoxynucleotidyl transferase (TdT) immunoperoxidase stains, we studied specimens from 25 children with ALL in morphologic remission to determine if we could identify children at risk of relapse. We studied morphologic remission bone marrow specimens from 9 patients who experienced relapse during the subsequent 6 months and 16 children who remained in complete remission, including 10 specimens with increased numbers of hematogones. Despite morphologic remission, clusters of more than 5 CD34+ and/or TdT-positive cells were identified before overt relapse in 6 of 9 cases of relapse, but were noted in only 1 of 10 specimens from children in continuous complete remission and none of 10 specimens with increased numbers of hematogones. Clusters of CD34+ or TdT-positive cells can identify individual patients at risk for imminent relapse. Hematogones may be differentiated from lymphoblasts by this method.