The present invention includes a diagnostic assay for the detection and determination of MGP in a human serum sample, which comprises the use of one or more antibodies, preferably monoclonal antibodies, specifically recognizing epitopes on and/or conformations of human Matrix Gla-Protein. A method is provided for using MGP-related antigens as biomarkers for certain diseases, for example, atherosclerosis and other vascular diseases, and angiogenesis/neogenesis in tumor development. Monoclonal antibodies of class IgG are described for use in the assay, which are defined herein as mAb3-15, mAb35-49[Glu], mAb35-49[Gla], mAb35-53[Glu], and mAb35-53[Gla]. Polyclonal antibodies and methods are also disclosed for measuring MGP in a human serum sample.