First-principles calculations were performed to examine defect formation energies and site preference of substitutional divalent cations M2+ (M = Mg, Cu, Zn, Cd, Sr, Pb, and Ba) in hydroxyapatite (HAp, Ca-10(PO4)(6)(OH)(2)) and carbonated apatite (CAp). All inequivalent substitutional sites of CO32- and M2+ were investigated to determine their most preferential sites. For all M2+ studied, their defect formation energies for the most stable substitutional sites were lower in CAp than in hydroxyapatite (HAp), demonstrating that M2+ are preferentially substituted into CAp over HAp. For Ca sites in CAp, correlations between the defect formation energies and Ca-O bond lengths showed that bigger and smaller M2+ than Ca2+ are preferentially substituted for Ca sites with longer and shorter bond lengths than those in HAp, respectively. In addition, Ca sites with lower coordination numbers than 6 are preferentially substituted by Zn2+ and Cu2+ that originally tend to form 4- or 5-fold coordination in their phosphate crystals. CO32- substitution is therefore likely to effectively stabilize substitutional foreign ions by modifying bond lengths and coordination numbers of Ca sites from those in pure HAp. These effects may play an important role in enhancing the M2+ solubility into CAp.