Diabetes Mellitus (DM) accelerates coronary artery disease (CAD) and atherosclerosis, the causes of most heart attacks. The biomolecules involved in these inter-related disease processes are not well understood. This study analyzes biomolecules in the sera of patients with CAD, with and without type (T) 2DM, who are about to undergo coronary artery bypass graft (CABG) surgery. The goal is to develop methodology to help identify and monitor CAD patients with and without T2DM, in order to better understand these phenotypes and to glean relationships through analysis of serum biomolecules. Aorta, fat, muscle, and vein tissues from CAD T2DM patients display diabetic-related histologic changes (e.g., lipid accumulation, fibrosis, loss of cellularity) when compared to non-diabetic CAD patients. The patient discriminatory methodology utilized is serum biomolecule mass profiling. This mass spectrometry (MS) approach is able to distinguish the sera of a group of CAD patients from controls (p value 10-15), with the CAD group containing both T2DM and non-diabetic patients. This result indicates the T2DM phenotype does not interfere appreciably with the CAD determination versus control individuals. Sera from a group of T2DM CAD patients however are distinguishable from non-T2DM CAD patients (p value 10-8), indicating it may be possible to examine the T2DM phenotype within the CAD disease state with this MS methodology. The same serum samples used in the CAD T2DM versus non-T2DM binary group comparison were subjected to MS/MS peptide structure analysis to help identify potential biochemical and phenotypic changes associated with CAD and T2DM. Such peptide/protein identifications could lead to improved understanding of underlying mechanisms, additional biomarkers for discriminating and monitoring these disease conditions, and potential therapeutic targets. Bioinformatics/systems biology analysis of the peptide/protein changes associated with CAD and T2DM suggested cell pathways/systems affected include atherosclerosis, DM, fibrosis, lipogenesis, loss of cellularity (apoptosis), and inflammation.