Hydroxyapatite (HAP) nanoparticles were successfully prepared without using organic modifiers by the combination of high-gravity reactive precipitation and hydrothermal method. The influences of the high-gravity level, the total reactant flow rate, the reactant flow rate ratio, and the reactant concentration on the preparation of HAP nanoparticles were systematically explored. The results showed that a high-gravity level of 3808-7774 m/s(2), a total reactant flow rate of 120-360 mL/min, a moderate reactant flow rate ratio of 0.6-1.67, and a low reactant concentration of 0.04-0.3 mol/L favored the formation of uniformly small HAP nanoparticles with a mean size of 55-110 nm and a narrow size distribution. The increase of the high-gravity level led to the initial rapid and following slight decrease of the mean particle size. The mean particle size first decreased and subsequently increased with increasing the total reactant flow rate, the reactant flow rate ratio, and the reactant concentration. The uniformity of HAP nanoparticles was mainly determined by the micromixing condition of reactants. It could be envisioned that high-gravity reactive precipitation combined with hydrothermal method would be promising in the commercial production of HAP nanoparticles.