<p>Type 2 diabetes mellitus (T2DM) is a dysfunctional metabolic disorder characterized by low-grade inflammation. Peripheral neuropathy (PN), nephropathy (NE), and retinopathy (RT) are prominent microvascular complications (MICs) associated with T2DM. Interleukin (IL)-29, IL-41, and raftlin are recently identified immunomodulators that are hypothesized to play a pathogenic role in T2DM, but the evidence is not conclusive. Therefore, a study was conducted to characterize serum levels of these markers in T2DM patients with and without MICs (PN, NE, and RT) and to explore their cross‑sectional associations with these MICs. In this case–control study, 154 T2DM patients were included and classified into five groups: 34 newly diagnosed patients (ND), 30 patients without MICs (DM), 30 PN patients, 30 NE patients, and 30 RT patients. In addition, a control group (HC) consisting of 60 individuals was included. Serum IL-29, IL-41, and raftlin concentrations were quantified using ELISA kits. Compared to HC, IL‑41 levels showed a consistent and significant elevation in T2DM groups, particularly in ND and NE patients, whereas IL‑29 and raftlin levels showed modest variations, most of which were not significant changes. Receiver operating characteristic curve analysis revealed that an area under the curve greater than 0.70 was recorded only for IL-41 in all T2DM patients, as well as in ND and DM patients. Logistic regression analysis demonstrated that elevated IL-41 and decreased raftlin levels were linked to significantly high and low odds ratios, respectively, in all patients, and in ND and DM patients. In contrast, no significant association was observed between MICs (PN, NE, and RT) and IL-29, IL-41, or raftlin. These findings suggest that IL-41 and raftlin may represent candidate biomarkers related to inflammatory and metabolic disturbances in T2DM and associated MICs. However, their biological and clinical relevance requires confirmation in larger longitudinal and mechanistic studies.</p>