In fracture-related infection, the goal is to obtain an infection-free functional limb. Amputation will be the best treatment choice when a satisfactory functional outcome is more likely after it than after limb salvage. However, evidence on this is limited and has low methodological quality, with heterogeneous protocols, study populations, and outcome variables. A satisfactory functional outcome after limb salvage is unlikely in patients that are not expected to achieve bone union and a minimum of protective sensation of the plantar and palmar surfaces of the foot and hand, respectively, as these factors are crucial for postoperative functionality. After amputation, the use of a well-fitting prosthesis is key for a satisfactory functional outcome. The main factors influencing this are the likelihood of prosthesis wear (in turn, strongly influenced by patient age and pre-amputation mobility), quality of the socket fit, and degree to which the external prosthesis replaces the amputated limb’s function. In fracture-related infection patients, most amputations are motivated by the expectation for infection eradication after failure of other procedures.