Background: Managing periprosthetic joint infections are variable in practices. Debridement, antibiotics, and implant retention (DAIR) is one of the favorable interventions. Given that the success rate of the two-stage revision total knee arthroplasty (rTKA) might be overestimated. The purpose of this study is to compare the success rate between DAIR and standard two-stage rTKA with a comparable intervention time. Methods: We retrospectively reviewed the consecutive knee periprosthetic joint infection cases which underwent DAIR or two-stage rTKA (all procedures were performed by the senior author) within 12 weeks since their primary TKA between July 2009 and October 2019. Average follow-up was 72.20 ± 40.70 months (range 29–148 months) in the DAIR group compared to 89.14 ± 43.06 months after spacer insertion (range 29–163 months) in the two-stage revision group (P = 0.156). According to different interventions, demographic data; timing of surgical intervention; hospital for special surgery knee score; and success rate were collected and compared between the DAIR group and two-stage revision group. Failure of treatment was based on the Delphi consensus and the fate of spacers. The pathogen types and failure cases were also recorded and analyzed. Results: Average follow-up was 72.20 ± 40.70 months (range 29–148 months) in the DAIR group compared to 89.14 ± 43.06 months after spacer insertion (range 29–163 months) in the two-stage revision group. Time from index surgery was 3.90 ± 2.92 weeks (range 0–12 weeks) in the DAIR group, and 5.11 ± 2.86 weeks (range 0–12 weeks) in the 2-stage exchange group, respectively. The success rate was 70.0% and 75.0% in the DAIR group and two-stage revision group, respectively. But no significant differences were observed between the two groups. Conclusion: DAIR demonstrated comparable effectiveness with two-stage rTKA. We recommended DAIR as a choice for patients with current infection within 12 weeks after primary TKA. For methicillin-resistant staphylococcal infections and fungal infections, two-stage rTKA might be preferred.