AbstractLymphatic vessels play a key role in maintaining tissue‐fluid homeostasis, immune surveillance and metastasis. The hyaluronan receptor, LYVE‐1, is widely used as a molecular marker for adult and embryonic lymphatic endothelium, but its physiological functions have not yet been established in vivo. In agreement with a recent report, LYVE‐1−/− mice, which are healthy and fertile, do not display any defects related to congenital abnormalities of the lymphatic system. One hypothesis for the absence of a phenotype in LYVE‐1 null mice is that other hyaluronan receptors, such as CD44, may compensate for LYVE‐1. To test this hypothesis, we created LYVE‐1/CD44 double knockout mice with appropriate littermate controls. Lymphatic vessel structure and function, as determined by histological methods and intravital microscopy, show that LYVE‐1−/−, CD44−/− and LYVE‐1−/−/CD44−/− mice are indistinguishable from wild‐type mice under normal conditions. Furthermore, resolution of carrageenan‐induced paw edema is comparable in all genotypes. However, LYVE‐1−/−/CD44−/− mice exhibit increased edema formation in a carrageenan‐induced paw inflammation model compared to wild‐type mice, but not to LYVE−/− or CD44−/− mice. These data suggest that LYVE‐1 and CD44 are not required for the formation or function of lymphatics, but do not rule out a role for LYVE‐1 in inflammation. J. Cell. Physiol. 219: 430–437, 2009. © 2009 Wiley‐Liss, Inc.