Despite improvements in first-line therapies, published results on the treatment of relapsed adult acute lymphoblastic leukemia (ALL) show that prognosis is still poor. The aim of the present retrospective analysis of the German Multicenter Study Group for Adult ALL was to identify prognostic factors and options for improvement. A total of 547 patients with a median age of 33 years (range, 15-55) experiencing their first relapse (406 vs 141 shorter or longer than 18 months from diagnosis) were evaluated. The aim of salvage therapy was to achieve a complete remission (CR) with subsequent a stem cell transplantation (SCT). The CR rate (assessed in Philadelphia chromosome– and BCR-ABL–negative ALL without CNS involvement) after the first salvage in relapse after chemotherapy (n = 224) was 42%. After failure of first salvage (n = 82), the CR rate after second salvage was 33%. In relapse after SCT (n = 48) the CR rate after first salvage was 23%. The median overall survival after relapse was 8.4 months and survival was 24% at 3 years. Prognostic factors for survival were relapse localization, response to salvage, performance of SCT, and age. Overall survival appeared superior compared with previously published studies, likely because of the high rate of SCT in the present study (75%). Further improvement may be achieved with earlier relapse detection and experimental approaches in early relapse. The study is registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.