AMD3100 is a reversible inhibitor of the binding of SDF-1α to its cognate receptor CXCR4. Patients with MM and NHL given AMD3100 alone have increased circulating C D34+ cells. The purpose of the present study is to determine if AMD3100 added to a chemotherapy and G-CSF mobilization regimen can increase the circulating levels of PBSC, and the removal of such cells by leukapheresis. The only change to the standard care is the addition of AMD3100 to a cyclophosphamide (2.5 g/m2) mobilization for MM and either (R)ESHAP or (R)ICE in the case of NHL. In both arms G-CSF is given at 10 mcg/kg/d. AMD3100 is given after the first apheresis collection. To date, 10 patients (8 MM, 2 NHL) have completed the mobilization phase of the protocol. During recovery the mean number of PB CD34+ cells/μL was 191. This rose to 304 [2.0 fold increase, p=0.008] following the administration of AMD3100. The baseline collection resulted in a mean of 16.7 x 106 CD34+ cells/kg. This rose to 24.0 [1.8 fold increase, p=0.007] following the administration of AMD3100. Historic controls with MM receiving cyclophosphamide (4 g/m2), etoposide (400 mg/m2) and G-CSF had an inferior collection on day 2 [37.9 x 106 CD34+ cells/kg day 1 vs. 29.5 day 2, p=0.009]. Untoward events related to the combination of chemotherapy, G-CSF, and AMD3100 have not been noted. The 9 patients transplanted following this mobilization strategy have achieved an ANC > 500 at a median of 10 days, and platelet independence (>20k) at a median of 11 days. Validation of this strategy continues in additional patient cohorts to assess alternative AMD3100 administration schedules and to define CD34+ cell recruitment/release during recovery from mobilizing chemotherapy.