Collagen is the most abundant protein in the cell and the main cargo of the secretory pathway, contributing to hepatic fibrogenesis due to extensive deposition of extracellular matrix (ECM). Here we investigated the possible contribution of the unfolded protein response (UPR), the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum (ER), to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl4) administration or by high fat diet. Proteomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), as a major IRE1-regulated gene, a critical factor involved in collagen maturation. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB in the regulation of collagen production and its role in the pathogenesis of various disease states.