Some pediatric sarcoma patients have a high relapse rate despite initial response to chemotherapy. Adjunctive immunotherapy may aid in eradicating minimal residual disease in these cases. We have previously reported severe lymphocyte depletion and delayed immune recovery post chemotherapy. PBPC infusions post chemotherapy rapidly reconstitute trilineage hematopoiesis. This study was undertaken to characterize immune reconstitution in patients post-chemotherapy/PBPC infusions. Seventeen sarcoma patients underwent 5 cycles of induction therapy with vincristine, adriamycin, cyclophosphamide(VAdriaC) and G-CSF assisted PBPC harvest during the recovery period. This was followed with up to 3 cycles of consolidation therapy with melphalan, ifosfamide, etoposide (MIME) and PBPC infusions. A mean of 13.1 × 106 CD34 cells/kg, 9.1 × 106 CD4+cells/kg, and 9.2 × 106 CD8+ T cells/kg were administered per infusion. Immunologic assessment was followed pre, during and post therapy. Pre-therapy, mean numbers of peripheral blood CD4+ and CD8+ T cells were within normal limits(CD4+=664±59, CD8+= 334±45 cells/mm3) but there was severe depletion of these subsets during VAdriaC therapy (CD4+=105±37 and CD8+=67±34 cells/mm3), at one month (CD4+=73±40, and CD8+=70±65 cells/mm3)and at 3 months post MIME/PBPC therapy(CD4+= 100±34 and CD8+=190±65 cells/mm3). Functionally, the proliferative response to PHA, compared to control (ratio× 100), decreased from a mean of 155±26% pre therapy to less than 30% during and up to 3 months post therapy. In summary, chemotherapy induces severe CD4+ T-cell depletion which persists for at least 3 months despite infusion of PBPC containing hematopoietic progenitors and some mature T cells. In these patients, immunotherapy-based eradication of the minimal residual disease post intensive chemotherapy may require efforts beyond autologous PBPC infusion in order to rapidly reconstitute immune function.