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The bioactive coating of calcium phosphate cement (CPC) is a promising approach to enhance the bone-healing properties of bone substitutes. The purpose of this study was to evaluate whether coating CPCs with bone sialoprotein (BSP) results in increased bone formation. Forty-five female C57BL/6NRj mice with an average age of six weeks were divided into three groups. Either a BSP-coated or an uncoated three-dimensional plotted scaffold was implanted into a drilled 2.7-mm diameter calvarial defect, or the defect was left empty (control group; no CPC). Histological analyses revealed that BSP-coated scaffolds were better integrated into the local bone stock eight weeks after implantation. Bone volume/total volume (BV/TV) ratios and bone thickness at the bone&#8315;implant contact were analyzed via micro computed tomography (&#181;CT) after eight weeks. BSP-coated scaffolds and uncoated CPC scaffolds increased bone thickness in comparison to the control (CPC + BSP: 691.1 &#177; 253.5 &#181;m, CPC: 603.1 &#177; 164.4 &#181;m, no CPC: 261.7 &#177; 37.8 &#181;m, <i>p</i> &lt; 0.01). Accordingly, BV/TV was enhanced in both scaffold groups (CPC + BSP: 1.3 &#177; 0.5%, CPC: 0.9 &#177; 0.5%, no CPC: 0.2 &#177; 0.3%, <i>p</i> &lt; 0.01). The BSP coating showed a tendency towards an increased bone thickness (<i>p</i> = 0.18) and BV/TV (<i>p</i> = 0.18) in comparison to uncoated CPC scaffolds. However, a significant increase in bone formation through BSP coating was not found.