The term amyloidoma applies to localized deposits of amyloid in the absence of systemic amyloidosis. Skeletal and soft tissue amyloidomas are very rare and the pathogenesis is usually associated with lymphoproliferative disorders or because of local chronic inflammation. Due to the rarity of the disease and the limited application of proteomics for diagnostic purposes, it is difficult to find datasets of mass spectrometry-based characterization of amyloidomas. Here we report the histological and immunohistochemical features of four cases of musculoskeletal amyloidoma in association with laser capture microdissection (LCM) and bottom-up microproteomics. Proteomics techniques allowed to elucidate the nature of the amyloid protein deposit, improving the results obtained by immunohistochemistry (IHC). IHC results were confirmed in two cases while laser-capture microdissection coupled with bottom-up microproteomics was necessary to type the other two cases, for which IHC was inconclusive.