Circulating miRNAs have attracted attention as serum biomarkers for several diseases. In this study, we aimed to evaluate the diagnostic value of circulating miRNA-21 (miR-21) as a novel biomarker for elderly patients with type 2 cardiorenal syndrome (CRS-2). A total of 157 elderly patients with chronic heart failure (CHF) were recruited for the study. According to an estimated glomerular filtration rate (eGFR) cutoff of 60 ml/min/1.73 m 2 , 84 patients (53.5%) and 73 patients (46.5%) were assigned to the CRS group and the CHF group, respectively. Expression levels of serum miR-21 and biomarkers for CRS, such as kidney injury factor-1 (KIM-1), neutrophil gelatinase-related apolipoprotein (NGAL), cystatin C (Cys C), amino-terminal pro-B-type natriuretic peptide (NT-proBNP), N-acetyl-κ-D-glucosaminidase (NAG), and heart-type fatty acid-binding protein (H-FABP), were detected. Serum miR-21, KIM-1, NGAL, Cys C, NT-proBNP and H-FABP levels were significantly higher in the CRS group than in the CHF group (P < 0.01), whereas NAG expression was not significantly different between the two groups (P > 0.05). Cys C, H-FABP and eGFR correlated significantly with miR-21 expression, but correlations with miR-21 were not significant for NT-proBNP, NGAL, NAG and KIM-1. Moreover, multivariate logistic regression found that serum miR-21, increased serum Cys C, serum KIM-1, hyperlipidaemia and ejection fraction (EF) were independent influencing factors for CRS (P < 0.05). The AUC of miR-21 based on the receiver operating characteristic (ROC) curve was 0.749, with a sensitivity of 55.95% and a specificity of 84.93%. Furthermore, combining miR-21 with Cys C enhanced the AUC to 0.902, with a sensitivity of 88.1% and a specificity of 83.6% (P < 0.001). Our findings suggest that circulating miR-21 has medium diagnostic value in CRS-2. The combined assessment of miR-21 and Cys C has good clinical value in elderly patients with CRS-2. The term cardiorenal syndrome (CRS) refers to different clinical conditions in which heart and kidney dysfunction overlap. Ronco et al. proposed classifying CRS into 5 subtypes based on the potential underlying pathophysiologic mechanisms 1. Among these subtypes, type 2 cardiorenal syndrome (CRS-2) is characterized by chronic abnormalities in cardiac function that result in kidney injury or dysfunction, along with clinical manifestations of CHF and an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m 2 2. Furthermore, the incidence of renal insufficiency increases to 45-63% for elderly CHF patients with hypertension, diabetes, atherosclerotic heart disease and lipid metabolism diseases 3-5. Assessment of kidney injury in CHF patients has previously been limited to serum creatinine, urea nitrogen and urinary protein excretion assays, which are prognostic for renal outcomes in CKD patients but not in heart failure patients 6. However, novel kidney biomarkers (Cys C, NGAL, KIM-1, H-FABP and NAG) have recently been evaluated in CHF patients, and their serum levels have prognostic value for not only r...