The relative risk of age, sex, underlying diagnosis, corticosteroid usage, diabetes mellitus, and major nonprosthetic infection for the development of multiple prosthetic infections was assessed retrospectively. Deep infection occurred in 174 replacement arthroplasties in 145 patients between 1981 and 1993. Patients with rheumatoid arthritis had a significantly larger number of implants per patient (P < .001). Twenty-seven of 145 patients developed a second prosthetic infection, for an overall incidence of 19%. Of these 27, the underlying diagnoses were rheumatoid arthritis in 19, osteoarthritis in 6, neuropathic arthritis in 1, and systemic lupus erythematosus in 1. Rheumatoid arthritis and the occurrence of a major nonprosthetic infection (sepsis) were found to be highly associated with the development of a second prosthetic infection (P < .001 and P = .0001, respectively). In those rheumatoid patients with multiple infections, there was a significantly larger proportion with American Rheumatism Association class III and IV function than those with a single prosthetic infection (P = .0002). In 14 of the 27 cases of more than one prosthetic infection, the infected implants presented clinically within the same month. Ten of these 14 had an associated nonprosthetic infection. It is therefore not possible to accurately calculate the risk that one infected arthroplasty poses to other implants.