The CFTR High Expresser (CHE) cells express 8-fold higher levels of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl^- channel compared to neighboring enterocytes, and were first identified by our laboratory (Ameen et al 1995, Gastroenterology 108:1016). We used double label immunofluorescence microscopy to further study these enigmatic epithelial cells in rat intestine in vivo or ex vivo. CHE cells were found in duodenum, most frequent in proximal jejunum, and absent in ileum and colon. CFTR abundance increased in CHE cells along the crypt-villus axis. The basolateral Na⁺K⁺Cl^- co-transporter NKCC1, a key transporter involved in Cl^- secretion was detected at similar levels in CHE cells and neighboring enterocytes at steady state. Microvilli appeared shorter in CHE cells, with low levels of Myosin1A - a villus enterocyte specific motor that retains sucrase/isomaltase in the brush border membrane (BBM). CHE cells lacked alkaline phosphatase and absorptive villus enterocyte BBM proteins including: Na⁺H⁺ exchanger NHE3, Cl^-/HCO₃^- exchanger SLC26A6 (PAT1), and sucrase/isomaltase. High levels of the vacuolar-ATPase proton pump were observed in the apical domain of CHE cells. Levels of the NHE regulatory factor NHERF1, Na-K-ATPase and Syntaxin 3 were similar to that of neighboring enterocytes. cAMP or acetylcholine stimulation robustly increased apical CFTR and basolateral NKCC1 disproportionately in CHE cells relative to neighboring enterocytes. These data strongly argue for a specialized role of CHE cells in Cl^--mediated "high-volume" fluid secretion on the villi of the proximal small intestine.