This work reports the effects of phosphoserine addition on the biodegradability of calcium phosphate cements. The characteristics of a phosphoserine-modified calcium phosphate cement without collagen in a large animal model are presented here for the first time. Critical size bone defects in the proximal tibia of 10 sheep were filled with the bone cement, and five sheep with empty defects were included as controls. The sheep were sacrificed after either 10 days or 12 weeks, and bones were processed for histological, histomorphometric and enzyme histochemical analyses as well as transmission electron microscopic examination. After 12 weeks, there was no significant reduction in either the implant or the bone defect cross-sectional area. Different amounts of fibrous tissue were observed around the implant and in the bone defect after 12 weeks. The direct bone-implant contact decreased after 12 weeks (p = 0.034). Although the implanted material properly filled the defect and promoted an initial activation of macrophages and osteoblasts, the resorption and simultaneous substitution did not reach expected levels during the experimental time course. Although other studies have shown that the addition of phosphoserine to calcium phosphate cements that have already been modified with collagen I resulted in an acceleration of cement resorption and bone regeneration, this study demonstrates that phosphoserine-modified calcium phosphate cements without collagen perform poorly in the treatment of bone defects. Efforts to use phosphoserine in the development of new composites should take into consideration the need to improve osteoconduction simultaneously via other means.