We have expressed the human neurotrophin receptor p75 (p75(NTR)) in the intestinal epithelial cell line Caco-2 as a model to study intracellular transport and subcellular sorting signals in intestinal cells. p75(NTR) was localized at the apical membrane of Caco-2 cells and reached this membrane mainly via an indirect pathway. Apical localization, intracellular routing, and basolateral to apical transcytosis were not affected by truncation of the cytoplasmic domain or replacement of the transmembrane domain by a glycosyl phosphatidylinositol anchor. Removal of membrane anchoring resulted in basolateral secretion of the ectodomain of p75(NTR) in Caco-2 cells but in apical secretion in Madin-Darby canine kidney (MDCK) cells. Substitution of potential O-glycosylation sites present in the stalk of p75(NTR) led to intracellular cleavage and secretion of the ectodomain into the basolateral medium both in Caco-2 and MDCK cells. These results suggest that the stalk of p75(NTR) carries an apical sorting information that is recognized efficiently by Caco-2 cells only when attached to the membrane. This apical sorting information is linked to the presence of predicted O-glycosylation sites in that region. These putative O-glycosylation sites also play a role in the regulation of p75(NTR) transport to the cell surface and in the prevention of rapid degradation by cleavage of the stalk domain.