Modular megaprostheses (MPs) are commonly used after bone-tumor resection, but they can offer a limb salvage solution in massive bone defects. The aim of this systematic review of the Literature is to provide a comprehensive data collection concerning the use of MPs in non-oncologic cases, and to provide an overview of this topic, especially from an epidemiologic point of view. Three different databases (PubMed, Scopus, and Web of Science) were searched for relevant articles, and further references were obtained by cross-referencing. Sixty-nine studies met the inclusion criteria, reporting on cases of MP in non-oncologic cases. A total of 2598 MPs were retrieved. Among these, 1353 (52.1%) were distal femur MPs, 941 (36.2%) were proximal femur MPs, 29 (1.4%) were proximal tibia MPs and 259 (10.0%) were total femur MPs. Megaprostheses were most commonly used to treat periprosthetic fractures (1158 cases, 44.6%), in particular in the distal femur (859, 74.2%). Overall, complications were observed in 513 cases (19.7%). Type I (soft tissue failures) and type IV (infection) according to the Henderson classification were the most frequent (158 and 213, respectively). In conclusion, patients with severe post-traumatic deformities and/or significant bone loss who have had previous septic complications should be considered as oncologic patients, not because of the disease, but because of the limited therapeutic options available. The benefits of this treatment include relatively short operative times and immediate weight-bearing, thus making MP particularly attractive in the lower limb.