Objective To investigate the significance of sensory neuropeptides [calcitonin gene related peptide (CGRP) and substance P (SP)] in steroid-induced avascular necrosis of the femoral head (ANFH) by using a rabbit model. Methods Fifty-five adult female Japanese White rabbits (weighing 3 kg and aging 24 months) were randomly divided into experimental group (n=45) and control group (n=10). The rabbits in experimental group received a single intramuscularinjection of methylprednisolone at a dose of 4 mg/kg and then were sacrificed after 3 days (n=15), 1 week (n=15), and 2 weeks (n=15) of injection. The rabbits in control group were fed without any treatment. The necrosis of the femoral head was observed. And the expressions of the monoclonal antibodies CGRP and SP were observed with immunohistochemical staining. Also, the integrated absorbance (IA) value of the positive area was calculated. Results All rabbits survived to the end of the experiment. There was no necrosis of the bone or bone marrow in experimental group at 3 days; whereas ANFH was observed in 5 rabbits at 1 week (33%) and in 8 rabbits at 2 weeks (53%). There were significant differences in the rate of ANFH between 1 week, 2 weeks and 3 days (P lt; 0.05); but there was no significant difference between 1 week and 2 weeks (P gt; 0.05). The intensity of CGRP immunoreactivity increased and reached the peak at 1 week, and then decreased at 2 weeks in experimental group. The IA value of CGRP in experimental group at 1 week was significantly higher than that of control group and that of experimental group at 3 days (P lt; 0.05). The IA value of CGRP in experimental group at 2 weeks was significantly lower than those at 3 days and 1 week (P lt; 0.05). The intensity of SP immunoreactivity decreased and reached the lowest at 1 week, and then increased. The IA value of SP in experimental group at 1 week was significantly lower than that of control group and that of experimental group at 2 weeks (P lt; 0.05). Conclusion The sensory neuropeptides may be affected by the steroid, which may play a key role in the process of steroid-induced ANFH by imbalance of bone metabol ism, disturbance of the microcirculation of bone, and disorder of the protective pain-transmission.