Previous studies indicated that nonsteroidal anti-inflammatory drugs (NSAIDs) suppress bone repair, growth, and remodeling in vivo. Our previous in vitro study demonstrated that indomethacin and ketorolac inhibited osteoblast proliferation. In this study, we further investigated the influences of 4 NSAIDs on cell cycle kinetics, cytotoxicity, and cell death pattern in osteoblast cultures from rat fetal calvaria. Our results showed that NSAIDs significantly arrested cell cycle at the G(0)/G(1) phase and induced cytotoxicity and cell death of osteoblasts. Apoptosis was more pronounced than necrosis caused by NSAIDs. Among these NSAIDs, piroxicam showed the least effect to produce osteoblastic dysfunction. Moreover, we found that the cytotoxic and apoptotic effects of NSAIDs on osteoblasts might not be prostaglandin related. These results suggest that the NSAID effects on cell cycle arrest and cell death induction in osteoblasts may be one of the important mechanisms contributing to their suppressive effect on bone formation.