In this study, we found that Cysteine‐rich with EGF‐like domains 2 (CRELD2), a novel endoplasmic reticulum stress‐inducible protein, is not only localized in the ER‐Golgi apparatus but also spontaneously secreted. Deletion of four C‐terminal amino acids from mouse CRELD2 or addition of tag‐peptides to its C‐terminus dramatically enhanced CRELD2 secretion. Intra‐ and extra‐cellular CRELD2 is differentially glycosylated and its spontaneous secretion was significantly prevented by overexpression of a dominant negative mutant Sar1 and treatment with brefeldin A. Overexpression of wild‐type GRP78 remarkably enhanced the secretion of wild‐type but not mutant CRELD2. Our results demonstrate both that CRELD2 is a novel secretory glycoprotein regulated by Sar1 and GRP78 and that the C‐terminal of CRELD2 plays a crucial role in its secretion.