Objectives <p>To determine the relationship between serum Ism-1 levels and the progression of renal function decline in patients with T2DM.</p> Methods <p>This prospective longitudinal study included 223 patients with T2DM. Patients were divided into quartiles according to serum Ism-1 levels. A Cox proportional hazards ratio model was applied to analyze the relationship between CKD progression and serum Ism-1 levels.</p> Results <p>A total of 197 patients were finally analyzed, and the mean length of follow-up was 40.86 months. The serum Ism-1 levels were associated with eGFR decline and an increased risk of composite renal outcomes after adjusting for age, gender, body mass index, diabetes duration, history of hypertension, fasting blood glucose, fasting C-peptide, total cholesterol, triglycerides, drinking, smoking and follow-up period (all <i>p</i> &lt; 0.05). However, the predictive ability of Ism-1 for composite renal outcomes disappeared after adjusting for baseline eGFR in Cox regression analysis and receiver operating characteristic (ROC) curve analysis.</p> Conclusions <p>High serum Ism-1 may be a biomarker for the progression of renal function decline in patients with T2DM.</p> Clinical trial number <p>Not applicable.</p>