Results of second-line therapy for childhood acute lymphoblastic leukemia (ALL) remain suboptimal, particularly for high-risk groups identified using timing and site of relapse. We report results of prospectively collected data for pediatric patients with ALL who received risk adjusted second-line therapy. The 59 patients who failed first-line ALL therapy included 36 (61%) with bone marrow (BM), 13 (22.1%) with isolated extramedullary (EM) and 10 (16.9%) with BM + EM relapse. Some 51.8% patients were reinduced with high dose cytosine arabinoside (HDAraC)-based and 48.2% with standard four-drug regimens. In all, 38/56 (67.9%) achieved a complete remission (CR) with second-line therapy; the overall CR rate was 78.6% and was not associated with CR1 duration (p =0.8). Three-year overall survival (OS) was 45.3%, and was 61.4% for those achieving a CR. No risk group benefited from HSCT over chemotherapy. Patients with isolated EM relapse beyond 18 months of CR1 and BM relapse beyond 12 months off-therapy had an excellent outcome (OS 91.7%), identifying a particularly good-risk cohort. Patients not in this category continue with poor outcome even following hematopoietic stem cell transplant.