We aimed to analyze the efficacy and safety of high doses of daptomycin (10 mg/kg/d) plus rifampin (D10 + R) for prosthetic joint infection (PJI). This was an observational retrospective multicenter study (2010–2012) including all patients with acute PJI by fluoroquinolone-resistant staphylococci managed with implant retention and D10 + R. Twenty cases were included: 2 (10%) were withdrawn due to toxicity, leaving 18 cases for efficacy evaluation: 13 (72%) women, age 79 years (range 58–90). Clinical failure was observed in 9 (50%) patients: in 5 cases, staphylococci were recovered (28% of microbiological failures); no modification of daptomycin-MIC was observed. These 18 cases were compared with 44 matched historical cases: failure rate was similar, but whereas in the historical series, failure occurred fundamentally during therapy, in the present series, it was recorded after discontinuation of antibiotics. In summary, D10 + R may be the initial treatment of choice for PJI by fluoroquinolone-resistant staphylococci managed with implant retention.