Periprosthetic joint infection (PJI) is a catastrophic complication that can occur following total knee arthroplasty (TKA). Currently, the treatment for PJI mainly includes the use of antibiotics alone, prosthetic debridement lavage, primary revision, secondary revision, joint fusion, amputation, etc. To explore the clinical effect of two-stage revision surgery for the treatment of PJI after TKA. The clinical data of 27 patients (3 males and 24 females; age range, 47-80 years; mean age, 66.7 ± 8.0 years; 27 knees) with PJI treated with two-stage revision surgery in our hospital between January 1, 2010 and December 31, 2020 were analyzed retrospectively. The following outcomes were compared for changes between preoperative and last follow-up results: Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), visual analogue scale (VAS) scores, Hospital for Special Surgery (HSS) scores, knee range of motion (ROM), and infection cure rates. All 27 patients were followed up (range, 13-112 mo). The ESR (14.5 ± 6.3 mm/h) and CRP (0.6 ± 0.4 mg/dL) of the patients at the last follow-up were significantly lower than those at admission; the difference was statistically significant (P < 0.001). The postoperative VAS score (1.1 ± 0.7), HSS score (82.3 ± 7.1), and knee ROM (108.0° ± 19.7°) were significantly improved compared with those before the surgery; the difference was statistically significant (P < 0.001). Of the 27 patients, 26 were cured of the infection, whereas 1 case had an infection recurrence; the infection control rate was 96.3%. Two-stage revision surgery can effectively relieve pain, control infection, and retain good joint function in the treatment of PJI after TKA.