Clinical use of purified hematopoietic stem cells in myeloablated patients requires co-transplantation of short-term repopulating cells (STRCs) to ensure timely count recovery. Here, we investigated the flow fluorescence-based side population (SP) phenotype of mobilized human peripheral blood (mPB) cells that rapidly repopulate the highly permissive nonobese diabetic/severe combined immunodeficient (NOD/SCID)-β2 microglobulin ^-/- mouse. No SP cells from this source regenerated detectable progeny in these mice before 8 weeks, although by 12 weeks human B-lymphoid cells were seen in some recipients of SP mPB cells. All myeloid reconstituting activity, including that seen within 3 weeks after transplantation, was associated with the non-SP fraction. Isolation of SP cells depletes human mPB of the rapid myeloid reconstitution capacity provided by myeloid-restricted STRCs which are vital for early hematologic recovery in clinical transplant recipients.