Solid microspheres (diameter = 106-150 μm) of a Li(2)O-CaO-B(2)O(3) glass were reacted in a K(2)HPO(4) solution to form hollow hydroxyapatite (HA) microspheres. The effect of the temperature (25°-60°C), K(2)HPO(4) concentration (0.01-0.25M), and pH (9-12) of the solution on the diameter (d) of the hollow core normalized to the diameter (D) of the HA microspheres, the surface area, and the pore size of the microsphere wall was studied. The statistically significant process variables that influenced these microstructural characteristics were evaluated using a factorial design approach. While the pH had little effect, the concentration of the solution had a marked effect on d/D, surface area, and pore size, whereas temperature markedly influenced d/D and pore size, but not the surface area. The largest hollow core size (d/D value ≈ 0.6) was obtained at the lowest temperature (25°C) or the lowest K(2)HPO(4) concentration (0.02M), while microspheres with the highest surface area (140 m(2)/g), with pores of size 10-12 nm were obtained at the highest concentration (0.25M). The consequences of these results for potential application of these hollow HA microspheres as devices for local delivery of proteins, such as drugs or growth factors, are discussed.