BACKGROUND: The purpose of this retrospective analysis of a prospective quality control project was to determine whether the use of intrawound vancomycin powder (IVP) decreases the rate prosthetic joint infection (PJI) within 90-days following primary total knee arthroplasty (TKA). METHODS: From October 2021-September 2022, a prospective quality control project was undertaken in which 10 high-volume arthroplasty surgeons alternated between using IVP and not using IVP each month. Patients who received IVP were compared to those who did not. The primary outcome was culture positive PJI within 90-days following primary total knee arthroplasty. Secondary outcomes included overall reoperation rate, wound complications, and readmission within 90-days post-operatively. RESULTS: A total of 1,317 primary TKA patients were identified for analysis. Fifty-six and seven tenths percent (n = 747) of patients were included in the IVP group and 43.3% (n = 570) patients were included in the non-IVP group. The overall PJI rate was 0.5%. There was no difference in 90-day culture positive PJI rates between the groups (0.7% vs. 0.2%, p = 0.24). The overall reoperation rate did not differ between the IVP and non-IVP group (6.4% vs. 4.6%, p = 0.15). Reoperation for suspected infection was not statistically different by IVP administration (1.2% vs. 0.5%, p = 0.25). Additionally, there were no differences in the incidence of wound complications (p = 0.80) or readmissions (p = 0.15). CONCLUSIONS: The overall infection rate for this cohort was low. IVP was not associated with decreased culture positive PJI, wound complications, reoperation or readmission rates. Further analysis of IVP use in TKA should be undertaken to fully determine its efficacy and safety profile.