Tubulointerstitial injury (TII) plays a crucial role in the progression of diabetic nephropathy (DN), but lack of specific and sensitive biomarkers for monitoring TII in DN management. This study is to investigate whether urinary decoy receptor 2 (uDcR2) could serve as a novel noninvasive biomarker for assessing TII in DN. We recruited 311 type 2 diabetics and 139 DN patients which diagnosed by renal biopsy. uDcR2 levels were measured by ELISA and renal DcR2 expression was detected immunohistochemically. Associations between uDcR2 and renal DcR2, renal functional parameters were evaluated. ROC curve analyzed AUC of uDcR2 for assessing TII. Double staining was undertaken for renal DcR2 with proximal and distal tubular markers, senescent markers p16, p21, and SA-β-gal, and fibrotic markers collagen I and IV. We found DcR2 was primarily expressed in renal proximal tubules; uDcR2 levels were elevated per albuminuria stratum and correlated with renal functional parameters in diabetics, and associated with percentage of tubular DcR2 and TII score in DN. The uDcR2 had an AUC of 0.909 for assessing TII in DN by ROC analysis. Almost all tubular DcR2 was co-expressed with p16 and p21, and nearly more than half of tubular DcR2 was positive for SA-β-gal, primarily in collagen I- and IV-positive regions of DN. Our results indicate uDcR2 could potentially serve as a novel biomarker for TII and may reflect senescence of renal proximal tubular cells in DN pathogenesis.