Background: Increasing evidence suggests that lymphocyte recovery plays a major part in tumor control. Facilitating immune reconstitution might be a novel direction of cancer therapy. The purpose of this study was to determine if early lymphocyte recovery is an independent prognostic indicator for high-risk Ewing sarcoma outcome., Results: Data of 24 Ewing sarcoma patients were analyzed (age, 3 to 50 y; median, 16.5; male to female, 16:8). The 5-year overall survival (OS) of the total population was 47.9% [10.6 standard error (SE)]. Patients were separated into 2 groups: prolonged lymphopenia versus early lymphocyte recovery, using a threshold absolute lymphocyte count (ALC) of > or =500 cells/microL on day 15. The majority (67%; n=16) of the patients had an ALC > or =500 cells/microL, and of these 10/16 are alive with a 5-year OS of 58.7% (13.2 SE). In contrast, 33% (n=8) of patients had an ALC <500 cells/microL on day 15 and only 2/8 are alive with a 5-year OS of 25% (15.3 SE). This difference was significant (P=0.007 using the log rank test). When comparing patients with metastatic disease, patients with an ALC-15 < 500 cells/microL had a median survival of 13 months, whereas patients with an ALC-15 > or =500 cells/microL had a median survival of 29.5 months. All patients had an ALC before chemotherapy of >1000 cells/microL. The difference was significant (P value=0.001 using the log rank test). Univariate analysis of platelet counts, age, sex, and absolute neutrophil count showed no statistically significant association with OS., Conclusions: The data demonstrate that an ALC > or =500 cells/microL on day 15 of the first course of chemotherapy is an independent prognostic factor associated with superior OS in high-risk Ewing sarcoma.