Background: Type 2 diabetes mellitus (T2DM) is a well-established risk factor for the development of atherosclerotic coronary artery disease. Platelet hyperactivity and inflammation are associated with the development of coronary artery disease (CAD) in T2DM patients. We investigated the status of immune cells, platelet activation, and plateletimmune cell interactions in T2DM_CAD patients. Methodology:The study population consisted of four groups of subjects, healthy control (CT, n = 20), T2DM (n = 44), CAD (n = 20) and T2DM_CAD (n = 38). Platelet activation, immunome profiling and platelet-immune cell interactions were analysed by flow cytometry. The circulatory levels of inflammatory cytokines/chemokines were assessed using multiplex assay. Results: Increased platelet activation and increased platelet-immune cell aggregate formation were observed in T2DM and T2DM_CAD groups compared to the control and CAD groups (p < 0.05). Our immunome profile analysis revealed, altered monocyte subpopulations and dendritic cell populations in T2DM, CAD and T2DM_CAD groups compared to the control group (p < 0.05). Furthermore, significantly increased IL-1β, IL-2, IL-4, IL-6, IL-8, IL12p70, IL-13 IL-18, CCL2, and decreased CXCL1, CCL5 levels were observed in T2DM_CAD group compared to the control group. Our ex-vivo study increased plateletmonocyte aggregate formation was observed upon D-glucose exposure in a time and concentration dependent manner. Conclusion: Our data suggests that T2DM, CAD and T2DM_CAD are associated with altered immune cell populations. Furthermore, it has been confirmed that hyperglycemia induces platelet activation and forms platelet-immune cell aggregation which may lead to the release of inflammatory cytokines and chemokines and contribute to the complexity of CAD and type 2 diabetes.