Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management during recovery from orthopaedic surgery. NSAID use is associated with increased risk of bone healing complications but it is currently unknown whether NSAIDs increase the risk of developing an orthopaedic-device-related infection (ODRI) and/or affects its response to antibiotic therapy. The present study aimed to determine if administration of the NSAID carprofen [a preferential cyclooxygenase-2 (COX-2) inhibitor] negatively affectedStaphylococcus epidermidis(S. epidermidis) bone infection, or its subsequent treatment with antibiotics, in a rodent ODRI model.Sterile orS. epidermidis-contaminated screws (~ 1.5 x 106CFU) were implanted into the proximal tibia of skeletally mature female Wistar rats, in the absence or presence of daily carprofen administration. A subset of infected animals received antibiotics (rifampicin plus cefazolin) from day 7 to 21, to determine if carprofen affected antibiotic efficacy. Bone changes were monitored usingin vivoµCT scanning and histological analysis. The risk of developing an infection with carprofen administration was assessed in separate animals at day 9 using a screw contaminated with 102CFUS. epidermidis. Quantitative bacteriological analysis assessed bacterial load at euthanasia.In the 28-day antibiotic treatment study, carprofen reduced osteolysis but markedly diminished reparative bone formation, although total bacterial load was not affected at euthanasia. Antibiotic efficacy was negatively affected by carprofen (carprofen: 8/8 infected; control: 2/9 infected). Finally, carprofen increased bacterial load and diminished bone formation following reducedS. epidermidisinoculum (102CFU) at day 9.This study suggests that NSAIDs with COX-2 selectivity reduce antibiotic efficacy and diminish reparative responses toS. epidermidisODRI.