Deep infection of megaprostheses remains a serious complication in orthopedic tumor surgery. Furthermore, reinfection gets a raising problem in revision surgery of patients suffering from infections associated with primary endoprosthetic replacement of the knee and hip joint. These patients will need many revision surgeries and in some cases even an amputation is inevitable. Silver-coated medical devices proved their effectiveness on reducing infections, but toxic side-effects concerning some silver applications have been described as well. Our study reports about a silver-coated megaprosthesis for the first time and can exclude side-effects of silver-coated orthopedic implants in humans. The silver-levels in the blood did not exceed 56.4 parts per billion (ppb) and can be considered as non-toxic. Additionally we could exclude significant changes in liver and kidney functions measured by laboratory values. Histopathologic examination of the periprosthetic environment in two patients showed no signs of foreign body granulomas or chronic inflammation, despite distant effective silver concentrations up to 1626 ppb directly related to the prosthetic surface. In conclusion the silver-coated megaprosthesis allowed a release of silver without showing any local or systemic side-effects.