The current study focused on doping of hydroxyapatite (HA) with constant yttrium (Y3+) and varying fluoride (F-) compositions to investigate its microstructure, microhardness, and biocompatibility. HA was synthesized by precipitation method and sintered at 1100 degrees C for 1 h. Y3+ and F- ion dopings resulted in changes in densities. In x-ray diffraction analysis, no secondary phase formation was observed. Lattice parameters decreased upon ion substitutions. Scanning electron microscopy (SEM) results showed that ion addition resulted in smaller grains. In Fourier transform infrared spectroscopy analysis, F- ion substitution was confirmed. HA doped with 2.5% Y3+ and 1% F- exhibited the highest microhardness. Y3+ and F- ions improved Saos-2 cell proliferation on discs in Methylthiazolyldi-phenyl-tetrazolium (MIT) assay. In SEM analysis, cells attached and proliferated on all disc surfaces. Alkaline phosphatase (ALP) assay showed that cell differentiation on the discs was improved by doping HA with an optimum F- amount. Dissolution tests revealed that structural stability of HA was improved with F- ion incorporation. The dissolution behavior of fluoridated samples exhibited a parallel pattern with the cell proliferation and differentiation behavior on these samples. Overall, this work shows that fluoride and yttrium cosubstitution into HA HA2.5Y1F was the most promising material for biomedical applications. (C) 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 96B: 207-217, 2011.