Background Identification of potential serum biomarkers of osteosarcoma to aid in its early diagnosis and in the discovery of possible therapeutic targets is an area of increasing interest.Methods Two-dimensional difference-in-gel electrophoresis was used to assess multiple serum samples in patients with osteosarcoma.In addition,differential expression of protein biomarkers was characterized in osteosarcoma serum by using matrix-assisted desorption/ionization time-of-flight mass spectrometry coupled with database interrogation.Serum samples from four individuals with osteosarcoma and four age- and sex-matched healthy control subjects were compared.Results Fifty-eight significant protein spot features in the osteosarcoma sera were found.These spot features were excised,digested with trypsin,and analyzed with mass spectrometry.Gelsolin was down-regulated only in osteosarcoma.Furthermore,Western blotting and enzyme linked immunosorbent assay (ELISA) confirmed decreased levels of gelsolin in the osteosarcoma serum samples.Conclusions These results indicated that gelsolin might have great potential as a biomarker of osteosarcoma and as a potential target for gene therapy.