In patients with osteoarthritis or arthritis, prosthetic joint replacement is increasingly used to alleviate pain and to improve mobility. The most important risk factors are comorbidity and prior joint replacement (revision surgery). Diagnosis of prosthetic-joint-associated infection is difficult, because the infecting agent may be missed in synovial fluid due to its exclusive presence as a device-associated biofilm. Implant-associated infections are difficult to treat because of their resistance to natural host defence mechanisms and to most antibiotics. In staphylococcal implant-associated infections a rifampin combination should be used, because this drug has an excellent efficacy on surface-adhering microorganisms. Antimicrobial therapy must always be combined with the correct surgical treatment which is chosen according to an algorithm. The use of antibiotics during procedures with potential bacteraemia is controversial because evidence for its need is lacking. In contrast, during sepsis rapid antibiotic therapy is needed to prevent haematogenous seeding on the artificial joint.