ABSTRACTInvolvement of the central nervous system (CNS) is a well-recognized complication of acute lymphocytic leukemia. We studied the patterns of such relapse in 56 children with acute lymphocytic leukemia whose disease was classified as E-rosette-positive or E-rosette-negative on the basis of whether their leukemic blasts formed rosettes with sheep erythrocytes. In the E+ group, CNS relapse was more frequent, and relapse occurred at, or sooner after, diagnosis and was more frequently followed shortly thereafter by bone marrow relapse. In addition, the E+ group was more likely to present with focal neurologic syndromes with or without blasts in the cerebrospinal fluid, in contrast to the more common features of diffuse meningeal leukemia with increase in intracranial pressure. These observations suggest that the E-rosette-positive lymphoblasts are more likely to infiltrate into nerve and brain tissue rather than invade the meninges diffusely. If confirmed, these findings imply that treatment of the CNS involvement may need to be different in patients with E+ acute lymphocytic leukemia than in patients with E- acute lymphocytic leukemia.