Background and Objectives: The placement of megaprostheses in patients with bone sarcoma is associated with high rates of infection, despite prophylactic antibiotic administration. In individual cases, secondary amputation is unavoidable in the effort to cure infection. Methods: The infection rate in 51 patients with sarcoma (proximal femur, n ¼ 22; proximal tibia, n ¼ 29) who underwent placement of a silver-coated megaprosthesis was assessed prospectively over a 5-year period, along with the treatment administered for infection. The infection rate was compared with the data for 74 patients in whom an uncoated titanium megaprosthesis (proximal femur, n ¼ 33; proximal tibia, n ¼ 41) was implanted. Results: The infection rate was substantially reduced from 17.6% in the titanium to 5.9% in the silver group. Whereas 38.5% of patients in the titanium group ultimately had to undergo amputation when periprosthetic infection developed, these mutilating surgical procedures were not necessary in the study group. Conclusions: The use of silver-coated prostheses reduced the infection rate in the medium term. In addition, less aggressive treatment of infection was possible in the group with silver-coated prostheses. Further studies with longer term follow-up periods and larger numbers of patients are warranted in order to confirm these encouraging results.