AbstractType 2 Diabetes Mellitus (T2DM) and Major Depressive Disorder (MDD) are highly disabling disorders associated with a multitude of vascular complications. Platelets are known to play a role in the pathogenesis of vascular complications in both T2DM and MDD. These complications could increase in patients with comorbid diabetes and depression. To quantify and compare flow cytometry based platelet activation markers and the inflammatory state between individuals of diabetes with depression, individuals of diabetes without depression and healthy controls. Out of 114 participants, each study group contained 38 participants in diabetic group, diabetics with depression group and matched control group. Diabetes was diagnosed with the American Diabetes Association (ADA) criteria. Screening of MDD was done with Patient Health Questionnaire 2 (PHQ2) and severity of depression assessed with Hamilton Depression Rating (HAM-D) scale. Platelet markers CD41, CD42b, CD62P and CD63 were assayed using flow cytometer. Platelet count, surface expression of platelet activation markers CD62P and CD63, hs-CRP, insulin and HOMA-IR score differed significantly between the groups. Post hoc analysis showed significantly high CD63 expression in patients with comorbid diabetes and depression compared to those having diabetes without depression. Patients with comorbid diabetes and depression have enhanced platelet hyperactivation and a pro inflammatory state which increases susceptibility to vascular complications.