Previously, we developed an apatite-coated non-porous poly(lactic-co-glycolic acid) (PLGA) microsphere (ANPM) as an injectable bone substitute. We hypothesized that an apatite-coated porous PLGA microsphere (APPM) would have enhanced osteogenic potential compared to that of an ANPM. To test the hypothesis, critical-sized bone defects were made in mouse calvaria, and APPMs and ANPMs were implanted in the defects for 8 weeks. New bone formed around both types of bone substitutes implanted in mouse calvarial defects. Importantly, the portion of bone-like tissue area in the implant cross-sectional area was significantly higher in the APPM group than in the ANPM group (36.9% versus 14.6%, P < 0.001). Fluorochrome-labeling analysis showed that bone regeneration occurred in the pores of implanted APPMs. The results show that APPM may be useful as a bone substitute in orthopedic applications.