Objective To explore the method and feasibility of establishing a peri-prosthetic infection model after total knee arthroplasty in New Zealand rabbits. Methods Forty-eight healthy New Zealand rabbits were randomly divided into three groups: an experimental group ( peri-prosthetic infection group), a control group ( non-peri-prosthetic infection group), and a blank control group (sham surgery group). A bacterial suspension of Staphylococcus aureus (0. 5 mL, 1 × 10⁷ CFU/ mL) was injected into the joint cavity of New Zealand rabbits 7 d after total knee arthroplasty in the experimental group, while 0. 5 mL saline was injected into the joint cavity of New Zealand rabbits 7 d after the total knee arthroplasty in the control group, and no treatment was undertaken after the capsule incision and suture of the knee joint in the blank control group. Hematology examination was performed 1 day before surgery and 7, 14, and 21 d after surgery in each group. X-ray examination, bacteriology, and pathology examination were performed 21 d after surgery. Results The survival rate of the experimental group was 87. 5% ( 14 / 16), and that of the control group and the blank control group was 100%. Twenty-one days after surgery, X-ray examination showed that the prosthesis was good in the experimental group and the control group, and there was no loosening around the prosthesis. The soft tissue around the joint was swollen in the experimental group, but not in the control group and the blank control group. Hematology examination showed that WBC, ESR, and CRP were significantly higher in the experimental group than in the control and blank control groups ( P< 0. 05). The bacteriological examination showed that the bacterial culture was positive in the experimental group, and the infection rate was 100% (14 / 14), while the infection rate was 6. 3% (1 / 16) in one case in the control group, and the bacterial culture was negative in the blank control group, with an infection rate of 0% (0 / 16). Pathological examination showed that there was a large amount of inflammatory cell infiltration around the prosthesis in the experimental group. Conversely, there was no inflammatory cell infiltration around the prosthesis in the control group and blank control group. Conclusions Injection of 0. 5 mL Staphylococcus aureus into the joint cavity 7 days after total knee arthroplasty in New Zealand rabbits was successfully established as a peri-prosthetic infection model after total knee arthroplasty.