Different combinations of irrigation solutions have been used in attempt to eradicate microorganisms for the prevention and treatment of prosthetic joint infections (PJIs). Clorpactin WCS-90 was evaluated as an alternative irrigation intraoperative technique for the treatment of PJI using both debridement, antibiotics, and implant retention (DAIR) and 2-stage total knee arthroplasty (TKA) procedures. We retrospectively reviewed PJIs irrigated with Clorpactin between January 2015 and January 2020. We found 13 patients who underwent a DAIR procedure for an acutely infected primary TKA, 18 patients underwent a 2-stage procedure for a chronically infected primary TKA, two patients underwent a DAIR procedure for an acutely infected revision TKA, and 18 patients underwent a 2-stage procedure for a chronically infected revision TKA. The odds of reinfection and need for additional surgery were analyzed at a mean follow-up of 20 to 26 months between groups. Only one patient (7.69%) became reinfected in the acute infected primary TKA group, three patients (16.67%) in the chronic infected primary TKA group, 0 patients (0%) in the acute infected revision TKA group, and six patients (33.33%) in the chronic infected revision TKA group. When the acute primary TKA infection group was compared with the chronic revision TKA infection group, the odds of reinfection (Chi-square test [χ2] = 21.7, df 3, p < 0.001) and odds of additional surgery (χ2 = 13.6, df 3, p < 0.003) were significantly higher for the chronic revision TKA infection group. Overall, the reinfection rate for DAIR revisions was 6.67% (range = 0-7.69) and 2-stage revisions was 25.00% (range = 16.67-33.33). The use of Clorpactin WCS-90 irrigation prior to wound closure is a useful option for the treatment of acute and chronic knee PJIs. Our study provides evidence that infection eradication with the use of Clorpactin is comparable to other irrigation methods and surgical techniques in reported literature.