TNFRSF6B overexpression in tumors is a novel predictor for poor prognosis in various cancers; however, whether TNFRSF6B could be expressed in kidney tissues of patients with chronic kidney disease is unknown. Current established risk factors cannot fully predict the progression of chronic kidney disease, and, therefore, it is mandatory to develop a newer marker for predicting disease progression. We conducted a prospective cohort study comprised 167 patients with chronic kidney disease undergoing renal biopsy at a tertiary hospital with median follow-up of 30.5 months. Computer-assisted quantitative immunohistochemical staining analysis of TNFRSF6B in kidney tissues, the expression of α-smooth muscle actin and percentage of fibrosis in renal interstitium, estimated glomerular filtration rate, and urinary protein excretion rate were investigated. Study endpoint was a doubling of serum creatinine and/or end-stage renal failure requiring renal replacement therapy. We found that TNFRSF6B was predominantly expressed in the tubular epithelial cells of renal cortex. The higher the expression of TNFRSF6B, the more the expression of α-smooth muscle actin and fibrosis in interstitium (P<0.001). Forty patients reaching endpoint had lower baseline estimated glomerular filtration rate and higher expression of TNFRSF6B in renal tubular epithelial cells. Multivariate Cox regression analysis showed that high expression of TNFRSF6B independently predicted the risk toward the renal endpoint with a hazard ratio of 3.46 (95% confidence interval (CI) 1.76-6.80, P<0.001) by adjusting for clinical and pathologic variables. While added to a model of estimated glomerular filtration rate, proteinuria and other conventional risk factors, TNFRSF6B further significantly improved the model predictability for progression of chronic kidney disease (area under the curve, 0.82). In conclusion, TNFRSF6B is associated with renal fibrosis and high expression of TNFRSF6B is a novel biomarker for predicting the progression of chronic kidney disease.