This study investigated the relationship between genetic polymorphism in the MDR1 (C3435T, G2677T) and the development of steroid-induced osteonecrosis of femoral head (ONF) in Chinese systemic lupus erythematosus (SLE) patients. 127 patients with active SLE, receiving 40 mg/day or more prednisolone were included. Patients were observed for the development of ONF by magnetic resonance imaging (MRI) and plain radiography first at three months after the beginning of steroid treatment and subsequently every year for five years. Genomic DNA was obtained from peripheral blood lymphocytes. The MDR1 2677G > T and 3435C > T genotypes were determined by the PCR-RFLP assay. 21 patients developed steroid-induced ONF. The incidence of ONF was significantly higher in steroid pulse therapy. The MDR1 3435 TT genotypes were significantly lower in the incidence of ONF (adjusted odds ratio = 0.14, 95% CI 0.017-1.153, p = 0.038). The MDR1 2677 TT was also lower in the incidence of ONF (adjusted odds ratio = 0.21, 95% CI 0.018-1.301, p = 0.05). Our findings suggest that MDR1 (ABCB1) gene polymorphisms can be used for predicting the development of ONF.