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One of the most commonly used treatments for acute prosthetic joint infection (PJI) is DAIR (debridement, antibiotics and implant retention), which comprises the debridement and the retention of the implant, followed by antibiotic treatment. The efficacy of DAIR remains unclear, as the literature has demonstrated variable success rates, ranging from 26% to 92%. The Staphylococcus aureus is one of the most closely related causative microorganisms, especially with acute and late-acute PJI; it has been identified as one of the most significant predictors of DAIR failure. The current guidelines consider the use of vancomycin as the therapy of choice, but it requires the close control of possible side effects. The aim of this study is to determine if a new combination of antibiotics (a highly bactericidal initial combination followed by an antibiofilm scheme) decreases the failure of DAIR-treated acute prosthetic joint infection (PJI) caused by Staphylococcus aureus. A retrospective analysis of cases of orthopedic infections during a nine-year period (2011–2019) was performed. A total of 45 acute PJI cases caused by S. aureus were diagnosed. The results of two antibiotic schemes were compared: a novel scheme comprising 5 days of daptomycin (10 mg/kg/24 h) + cloxacillin (2 g/6 h) followed by levofloxacin (500 mg/24 h) + rifampicin (600 mg/24 h), versus a traditional, less bactericidal scheme of vancomycin (1000 mg/12 h) plus rifampicin (600 mg/24 h) or levofloxacin (500 mg/24 h) plus rifampicin (600 mg/24 h). Twenty-two out of the twenty-four patients treated with the new scheme (91.6%) were free of infection after 24.8 months of mean follow-up, whereas fourteen out of twenty-one patients (66.6%) were free of infection after 46.6 months of follow-up. This difference was statistically significant (p = 0.036). Demographic comparisons demonstrated homogeneous features, except the Charlson score, which was higher in the novel scheme group (p = 0.047). The combination of high-dose daptomycin and cloxacillin, followed by levofloxacin plus rifampicin, together with surgical treatment, shows better results when compared with other antibiotic schemes for treating acute PJI caused by S. aureus in which DAIR was performed.