AbstractCyclooxygenase‐2 (COX‐2) plays major roles in diverse physiological and pathological processes such as inflammation and tumorigenesis. Transcriptional control of COX‐2 has been extensively investigated and characterized, but its post‐translational control is less clear. Here, we report a novel mechanism by which COX‐2 is degraded. Protein levels of caveolin‐1 (Cav‐1) and COX‐2 showed an inverse relation in colon cancer cell lines. COX‐2 proteins in lung and colon tissues were higher in Cav‐1 null mice than in wild‐type mice. RNAi knockdown of Cav‐1 increased COX‐2 protein level and decreased ubiquitinated COX‐2 accumulation. In addition, deletion of the carboxy (C)‐terminus of COX‐2, which contains a unique 19‐amino acid segment compared with COX‐1, resulted in reduced Cav‐1 binding and attenuated COX‐2 degradation. COX‐1 and green fluorescence protein containing the C‐terminus of COX‐2 resulted in enhanced degradation. Our findings suggest that Cav‐1 binds COX‐2 in endoplasmic reticulum (ER) and carries it for degradation via ER associated degradation. The C‐terminal region of COX‐2 is required for Cav‐1 binding and degradation. These results indicate a novel function of Cav‐1 in controlling COX‐2 expression, which may regulate physiological functions and have tumor suppression effects. J. Cell. Biochem. 109: 356–362, 2010. © 2009 Wiley‐Liss, Inc.