Addition of copper in biomaterials is currently investigated because it is expected to enhance the biological properties of bone graft substitutes. Copper-doped hydroxyapatite (CuHA) ceramics were prepared by high temperature solid-state reaction sintering between HA and CuO powder mixtures. The reaction occurred from 950 °C and copper-doped apatites were obtained up to 5.3 wt% of copper. For higher copper content, the presence of secondary phases of CuO and Cu2O remained in the material. Structural analyses (XRD, FTIR) showed the substitution of hydrogen by copper into the hydroxyapatite hexagonal channels in agreement with the following chemical composition Ca10(PO4)6CuIIzCuIyO2H2-2z-y with x = y + z and 0 ≤ x ≤ 0.7. Dense single phased apatitic HA ceramics containing up to 5.3 wt% of copper could be produced after natural sintering in air at 1100 °C. But, copper-substituted HA was found to be metastable leading to apatitic grains and Cu-rich grain boundaries during cooling to room temperature, which resulted in the formation of CuO grains at the material surface after annealing at 500 °C. Quenching from the sintering temperature was carried out to prevent this phenomenon and obtain ceramics made of single Cu-HA phase with a homogeneous fine grain microstructure. In vitro biological assays using MC3T3-E1 cells indicated that the sintered CuHA ceramics were biocompatible, neither cell adhesion nor proliferation being affected by copper addition. A negative effect on cell differentiation appears only from 5 wt% of copper in HA.