CCAAT-enhancer-binding protein delta (C/EBPd) is a transcription factor mainly known for its role in inflammation and apoptosis/proliferation. Considering that these are key processes in renal fibrosis, we hypothesized that C/EBPd would potentiate renal fibrosis. In line with this hypothesis, C/EBPd has recently been suggested to regulate the fibrotic response during glomerulonephritis. Here we determined the importance of C/EBPd in the development of renal tubulointerstitial fibrosis by subjecting 8-to 12-week-old C/EBPd-deficient mice and age-and sex-matched wild-type controls to the unilateral ureteral obstruction model. Mice were killed at 1, 3, or 7 days post surgery, and renal tissues were obtained for RNA, protein, and immunohistochemical analysis. We show that C/EBPd deficiency resulted in a more profound fibrotic response as evident from enhanced tubular injury, collagen deposition in the interstitial area, and higher expression of transforming growth factor-b. Moreover, we show that the increase in renal fibrosis in C/EBPd-deficient mice does not depend on an altered proliferation/apoptosis balance or on a differential inflammatory response in the obstructed kidney. In conclusion, our study provides direct evidence that C/EBPd is a novel mediator of renal fibrosis. Modulating C/EBPd expression could consequently be a potential antifibrotic strategy in patients with chronic kidney disease.