The overall incidence of osteomyelitis following primary knee arthroplasty is 1-2%. Major risk factors are large prostheses, rheumatoid arthritis, postoperative wound-healing complications, skin infections, and prior deep infections. The major infecting organism is Staphylococcus aureus. Healing of the infection is to be expected in 20% when systemic antibiotics alone are used, in 24% when soft tissue surgery is used, in 50% when resection arthroplasty is used, in 76% when revision arthroplasty is used, in 90% when arthrodesis is used, and in 100% when amputation is used. The direct medical costs average US$ 62,100 for an infected patient and US$ 8600 for a non-infected patient. Attention should focus on prophylactic measures directed towards the soft tissue problems: by avoiding conflicting skin incisions, by gentle handling of the periarticular soft tissues, by avoiding the use of constrained prostheses and oversized compartmental prostheses, by letting wound healing take priority over motion in knees with compromised soft tissues, and by using prophylactic antibiotic treatment for skin ulcers until these have healed.