AbstractAn overall decline in the availability of osteogenic precursor cells and growth factors in the bone marrow microenvironment have been associated with impaired bone formation and osteopenia in humans. The objective of the current study was to determine if transplantation of mesenchymal stromal cells (MSC) from a healthy, young donor mouse into an osteopenic recipient mouse could enhance osseointegration of a femoral implant. MSC harvested from normal young adult mice differentiated into bone forming osteoblasts when cultured on implant grade titanium surfaces ex vivo and promoted bone formation around titanium‐coated rods implanted in the femoral canal of osteopenic recipient mice. Micro computed tomographic imaging and histological analyses showed more, better quality, bone in the femur that received the MSC transplant compared with the contra‐lateral control femur that received carrier alone. These results provide pre‐clinical evidence that MSC transplantation promotes peri‐implant bone regeneration and suggest the approach could be used in a clinical setting to enhance bone regeneration and healing in patients with poor quality bone. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1183–1189, 2012