For a study, it was determined that Rifampin was basically recommended in the treatment of acute staphylococcal periprosthetic joint infections (PJI). However, if, when, and how to use rifampin remained a matter of concern. The researchers aimed to determine the results of patients cured with and without rifampin, and analysis of the influence of timing, dose, and co-antibiotic was done. Acute staphylococcal PJIs were treated with surgical debridement between 1999 and 2017, and a minimum follow-up of 1 year was examined. In total 669 patients were examined. Treatment failure resulted in 32.2% (131/407) in patients treated with rifampin and 54.2% (142/262) in whom rifampin was withheld (P<.001). The most adverse effect of rifampin was reported in the knees (treatment failure 28.6% vs 63.9%, respectively, P<.001). In the rifampin group, the use of a co-antibiotic other than a fluoroquinolone or clindamycin (OR 10.1, 95% CI 5.65–18.2) and the start of rifampin within five days after surgical debridement (OR 1.96, 95% CI 1.08–3.65) were the predictors of treatment failure. Information supported the use of rifampin in acute staphylococcal PJIs treated with surgical debridement, especially in knees.