To evaluate the impact of contemporary therapy on the clinical outcome of children with pre-B acute lymphoblastic leukemia (ALL) and the t (1; 19)/TCF3/PBX1, we analyzed 735 patients with B-cell precursor ALL treated in four successive protocols at St Jude Children's Research Hospital. The 41 patients with the t (1; 19) had a comparable event-free survival to that of the 694 patients with other B-cell precursor ALL (P= 0.63; 84.2±7.1%(se) vs 84.0±1.8% at 5 years). However, patients with the t (1; 19) had a lower cumulative incidence of any hematological relapse (P= 0.06; 0 vs 8.3±1.2% at 5 years) but a significantly higher incidence of central nervous system (CNS) relapse (P< 0.001; 9.0±5.1% vs 1.0±0.4% at 5 years). In a multivariate analysis, the t (1; 19) was an independent risk factor for isolated CNS relapse. These data suggest that with contemporary treatment, patients with the t (1; 19) and TCF3/PBX1 fusion have a favorable overall outcome but increased risk of CNS relapse.