Material-induced osteoinduction has been reported in comparatively large animals such as dogs and pigs; however, it does not often occur in small animals such as rodents. In this study, we implanted the porous calcium-deficient hydroxyapatite (CDHA) in the dorsal muscles of dogs and rats, and compared cellular events occurred in 2 species with particular emphasis on the osteoclast-like multinucleated cells. In the CDHA extracted from dogs, many tartrate resistant acid phosphatase (TRAP)-positive multinucleated cells were detected after 2 weeks, and new bone formation was observed after 4 weeks. In contrast, in rats, only a small number of TRAP-positive cells were detected and no bone formation was observed before 6 weeks. Transmission electron microscopy (TEM) revealed that multinucleated cells in the CDHA from dogs after 2 weeks showed osteoclast-like structures such as ruffled borders. However, in the CDHA from rats, there were no osteoclast-like structures observed. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that the expression of cathepsin K in dogs was higher than that in rats. These results indicate that TRAP-positive cells might be one of main factors responsible for the cross-species difference in material-induced osteoinduction.