CD63, also named LIMP-1, is a member of the tetraspanin superfamily, proteins that are regarded to be molecular facilitators involved in processes like cell activity, differentiation, adhesion and proliferation. Tetraspanins interact with many other proteins and are able to form so called tetraspanin webs. CD63 is mainly located in membranes of lysosomes and late endosomes. Mice deficient for CD63 (CD63 KO) are viable and fertile without gross morphological abnormalities in the majority of tissues. The lack of CD63 does not cause obvious endosomal/lysosomal alterations. Nevertheless in 24h metabolic cage experiments female, one year old CD63 knockout mice show an 2.7-fold increase in urinary flow (13127ml/24h/gBW) compared to wildtype animals (WT) (485ml/24h/gBW) paralleled by an 2.2-fold increase in water intake (24945ml/24h/gBW vs. 11417ml/24h/gBW). Urine electrolyte concentrations and urine osmolality are reduced to the halve indicating an increase in water diuresis. In addition, fecal water content is increased in CD63 KO (534.0%) in comparison to WT (362.5%). In principal cells of the collecting duct of CD63 KO abnormal intracellular lamellar inclusions were observed as a singular morphological finding. Immunostainings in isolated tubular segments revealed CD63 to be present in the whole nephron. Impaired water handling in intestine and kidney in CD63 KO suggests aquaporin vesicle trafficking as a potential pathophysiological mechanism.