Objective <p>We aimed to investigate the expression of lncRNA Kcnq1ot1 in T2DM patients with OA, as well as its correlation with serum inflammatory factors and clinical outcomes of the patients.</p> Methods <p>This prospective observational cohort study included a total of 50 patients with type 2 diabetes mellitus (T2DM), 50 patients with osteoarthritis (OA), and 51 patients with both T2DM and OA between March 2020 and March 2023. The serum TNF-α, interleukin (IL)-6, IL-1β and C-reactive protein (CRP) levels were measured using enzyme-linked immunosorbent assay (ELISA). To determine the expression of LncRNA Kcnq1ot1, RT-qPCR was used. Demographic, clinical statistics, lipid metabolism and nutritional indicators were collected. All data used SPSS 26.0 to statistical analyses.</p> Results <p>The T2DM + OA group had significantly higher BMI and LDLC levels compared to the T2DM group (<i>p</i> &lt; 0.05). The serum levels of LncRNA Kcnq1ot1 were significantly higher in the T2DM + OA group compared to the OA group and T2DM group (<i>p</i> &lt; 0.05). Pearson’s analysis supported a positive correlation between LncRNA Kcnq1ot1 and IL-6 and IL-1β levels. In addition, LncRNA Kcnq1ot1 could be a potential biomarker for diagnosing the occurrence of T2DM patients with OA. Moreover, LncRNA Kcnq1ot1, BMI, IL-6, Low density lipoprotein cholesterol (LDLC) were the risk factors for T2DM patients with OA.</p> Conclusion <p>This study showed that the serum LncRNA Kcnq1ot1 levels was remarkably elevated in T2DM patients with OA. This study might provide new targets and a comprehensive approach to treatment in T2DM patients with OA.</p>