OBJECTIVE To compare the effectiveness of calcium phosphate cement (CPC) loaded with recombinant human bone morphogenetic protein 2 (rhBMP-2) combined with CPC loaded with antibiotic versus CPC loaded with antibiotic alone in one stage for chronic osteomyelitis with bone defect. METHODS A single-blind prospective randomized controlled clinical trial was conducted. Between April 2018 and April 2019, 80 patients of chronic osteomyelitis with bone defect in accordance with the random number table were randomly divided into two groups, 40 in the trial group (CPC loaded with rhBMP-2 combined with CPC loaded with antibiotic) and 40 in the control group (CPC loaded with antibiotic). There was no significant difference in gender, age, disease duration, lesion, and preoperative white blood cells (WBC) count, platelet count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) between the two groups ( P>0.05). All patients were implanted the corresponding CPC and external fixator after lesion clearance in the two groups. The postoperative WBC count, platelet count, ESR, CRP, hospital stay, cure rate of osteomyelitis, repaired bone defect volume, the time of external fixator removal, and the time of full weight-bearing of the affected limb were compared between the two groups. RESULTS All patients were followed up 12-24 months, with an average of 18.4 months. There was no significant difference in WBC count, platelet count, ESR, and CRP between the two groups at 4 weeks after operation ( P>0.05). There were significant differences in WBC count, platelet count, and CRP in the two groups between 1 week before operation and 4 weeks after operation ( P<0.05). And the ESR showed no significant difference between pre- and post-operation in the two groups ( P>0.05). In the trial group, the anaphylactic exudate occurred in 1 patient with tibial osteomyelitis and the incision healed after oral administration of loratadine. The incisions of other patients healed by first intention in the two groups. One case of distal tibial osteomyelitis recurred in each group, and 1 case of humeral osteomyelitis recurred in the control group. The cure rates of osteomyelitis were 97.5% (39/40) in the trial group and 95% (38/40) in the control group, showing no significant difference between the two groups ( χ =0.000, P=1.000). There was no significant difference in the repaired bone defect volume and hospital stay between the two groups ( P>0.05). X-ray film and CT showed that the bone defects were repaired in the two groups. The time of external fixator removal and the time of full weight-bearing of the affected limb were significantly shorter in the trial group than in the control group ( P<0.05). CONCLUSIONS Application of CPC loaded with rhBMP-2 and antibiotic in one stage is effective for the chronic osteomyelitis with bone defect, which can accelerate the bone regeneration in situ to repair bone defect, reduce the trauma, shorten the course of treatment, and obtain good function of the affected limb.