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Background An appreciable proportion of patients in need of salvage high-dose chemotherapy (HDC) and autologous peripheral blood stem cell (PBSC) transplantation (PBSCT) fail to mobilize adequate numbers of hematopoietic progenitors, and plerixafor is applied for that purpose. Limited data exist on remobilization of PBSCs in patients who have relapsed after prior HDC + PBSCT. Herein, we report on consecutive patients that had undergone successful prior single or tandem HDC for a variety of malignant neoplasms in our institution, and later required re-mobilization of PBSCs in order to support further HDC cycles. Patients and Methods Plerixafor was administered in combination with granulocyte-colony stimulating factor alone, or after mobilizing chemotherapy. Five patients, 2 B-cell non-Hodgkin lymphomas, 1 multiple myeloma, 1 germ-cell tumor, and 1 Ewing sarcoma, having relapsed after prior HDC + PBSCT, were deemed candidates for further cycle(s) of PBSC-supported HDC. Plerixafor was applied in a “just-in-time” strategy after low CD34+ numbers were measured on the first day of anticipated hematopoietic stem cell collection (non-Hodgkin lymphoma, germ-cell tumor, and Ewing sarcoma), or pre-emptively in multiple myeloma. Results Successful collection of adequate PBSCs was achieved in all patients, from 1.8 to 3.8 × 106/kg after a median of 2 (range, 1-3) leukaphereses; 4 of 5 patients underwent subsequent HDC + PBSCT and engrafted after a median of 11 days (range, 9-55 days) and 25 days (range, 17-76 days) for neutrophils and platelets, respectively. Conclusion Plerixafor proved effective to mobilize adequate numbers of PBSCs in individual patients with relapsed malignancies after prior single or tandem HDC + PBSCT. These PBSCs could establish sustained multi-lineage hematopoietic engraftment without any sequelae.