Chronic inflammation and insulin resistance form hallmarks of type 2 diabetes mellitus (T2DM). An increased circulating level of the serine protease granzyme B (GzmB) is observed during prolonged inflammation and is implicated in the pathogenesis of several chronic inflammatory diseases. Moreover, insulin receptor cleavage by unknown proteases, yielding elevated levels of insulin receptor α-subunit (IRα), was observed in T2DM and was proposed as a new mechanism of insulin resistance. Therefore, a possible association between GzmB and IRα is suggested. Accordingly, this study was set to explore whether GzmB and IRα levels are altered in T2DM patients with the impact of obesity. Furthermore, we aimed to identify if GzmB contributes towards inflammation and insulin resistance through its suggested extracellular activities. All subjects were assessed for anthropometric and metabolic parameters related to obesity and T2DM. In addition, fasting plasma insulin, GzmB, interleukin-1β (IL-1β), and IRα levels were estimated by enzyme linked immunosorbent assay. Levels of GzmB and IRα were found to be significantly elevated in T2DM patients compared to nondiabetic subjects. In addition, GzmB levels were positively correlated with measures of obesity and insulin resistance, IL-1β, IRα, and other metabolic parameters. While multiple linear regression analysis revealed that both T2DM and central obesity were predicting factors for GzmB, our findings reveal a possible role of GzmB in T2DM.