Although uncommon, infection of prostheses with Mycobacterium tuberculosis can be managed successfully if it is diagnosed early and treated correctly. A case of M. tuberculosis infection of a prosthetic knee first diagnosed 4.5 years after initial arthroplasty is described. This case and a review of the literature led to the conclusion that there are two distinct patterns of M. tuberculosis infection following joint implant surgery in patients without a history of tuberculosis. (1) Mycobacterium tuberculosis infection may be an unexpected finding at the time of arthroplasty. These patients generally have favorable outcomes using standard antituberculous chemotherapy, without implant removal. (2) Late-onset M. tuberculosis joint infection may be identified in patients with painful, clinically infected, or malfunctioning prostheses. In these cases, medical treatment alone is usually unsuccessful; prosthesis removal is often required. With recent increases in the incidence of tuberculosis in the United States and the emergence of multidrug-resistant strains of M. tuberculosis, periprosthetic tuberculous infection is likely to become more common.