Background: Disease relapse is the major cause of failure after allogeneic hematopoietic stem cell transplantation (SCT) for acute lymphoblastic leukemia (ALL). Treatment options for these patients (pts) are limited and only a second SCT provides a realistic chance for long term disease remission. Methods: We retrospectively analyzed the outcomes of 31 pts with ALL who relapsed following their first allogeneic SCT, and went on to receive a second allogeneic SCT. Univariate analysis was used to assess for risk factors which influenced treatment-related mortality (TRM), and progression free survival (PFS) following second SCT. Results: 31 pts were evaluable for response with 2 early deaths within 30 days of SCT. The median age of the pts was 26 years (range 7- 49), and the median duration between their first SCT (SCT1) to relapse was 9.5 months (range 2.2-32.6 months). 39% of pts were transplanted in active disease (n=12). The complete remission (CR) rate post SCT was 89%; 83% of pts transplanted with active disease attained CR. With a median follow-up of 3 years among survivors, PFS, and OS rates at 1 year were estimated at 23%. The TRM rate was 41% at 12 months. We did not identify any factors that impacted TRM through univariate analysis. We found a significant relationship between the time to progression following SCT 1 and PFS following SCT 2 (p=0.02, HR=0.93/month). Conclusions: In summary, a second transplant remains an effective method for achieving response in a highly refractory patient population. Pts with longer PFS following SCT1 have a better PFS following SCT2. While long-term survival is limited, a significant proportion of pts remain disease-free for up to one year following SCT2, providing a window of time to administer preventive interventions. Notably, our 4 long-term survivors, received novel therapies in the form of a single umbilical cord blood unit in addition to the PBSC to augment the immune response (n=2), a change in the stem cell source for the SCT from cord to mismatched adult unrelated (n=1), and post SCT maintenance therapy with 5-azacytidine (n=1), underscoring the need for a fundamental change with the methods for the second transplant to improve outcome.