Of the 6075 patients enrolled in EU-CORE registry, 206 patients had orthopaedic device-related infections. Significant underlying diseases were reported in 71% patients, most frequently cardiovascular disease (38%). The common sites of infection were knee (40%) and hip (33%). Among the 170 patients with available culture results, 135 (79%) were positive. Coagulase-negative staphylococci (CoNS, 44%) and Staphylococcus aureus (43%, of those 47% were methicillin resistant) were the most commonly isolated pathogens. Daptomycin was used empirically in 48% patients and as second-line therapy in 67% patients. During daptomycin therapy, 67% patients had undergone surgery (debridement, 61%; removal of foreign device, 39%; incision and drainage, 9%). Over half of the inpatients (54%) received concomitant antibiotics. Daptomycin was most frequently prescribed at a dose of 6 mg/kg/day (48%), with a median duration of therapy of 16 (range, 1–176) days. The overall clinical success rate was 85%, and was similar whether daptomycin was administered as first- or second-line therapy. The success rates achieved for infections caused by S. aureus and CoNS were 86% and 83%, respectively. Among the 79 patients who entered the long-term follow-up, 85% had a sustained response. Adverse events (AEs) and serious AEs possibly related to daptomycin were reported in 4.4% and 1.9% patients, respectively. Results from this real-world clinical experience showed that daptomycin is an effective and well-tolerated treatment option for orthopaedic device-related infections with a high success rate up to 2 years of follow-up.