Current problems associated with bone allografts include risk of disease transmission, limited availability, and cost. Synthetic scaffolds have been proposed as substitute graft materials to address these issues. Calcium polyphosphate is a novel synthetic scaffold material that has shown good mechanical properties and biocompatibility. Here, we evaluated calcium polyphosphate in terms of its ability to support cell proliferation and differentiation in vivo. Calcium polyphosphate, morsellized cancellous bone, and hydroxyapatite/tricalcium phosphate particles were seeded with marrow stromal cells and implanted subcutaneously in the back of NOD/Scid mice. At 7, 14, and 28 days the samples were harvested and the proliferation characteristics and gene expression were analyzed. All tested graft materials had similar proliferation characteristics and gene expression. The subcutaneous environment had a stronger impact on the proliferation and differentiation of the cells than the scaffold material itself. However, it was shown that calcium polyphosphate is superior to hydroxyapatite/tricalcium phosphate and bone in its ability to support cell survival in vivo. The study confirmed that calcium polyphosphate has potential for replacing morsellized cancellous bone as a graft material for bone regeneration.