Phosphate reabsorption in the renal proximal tubule occurs mostly via the type-IIa sodium-phosphate cotransporter (NaPi-IIa) in the brush border membrane (BBM). The activity and localization of NaPi-IIa is regulated among other factors by parathyroid hormone (PTH). NaPi-IIa interacts in-vitro via its last three C-terminal amino acids with the PDZ-protein Na⁺/H⁺-Exchanger isoform 3 Regulating Factor 1 (NHERF1). Renal phosphate reabsorption in NHERF1 deficient mice is altered and NaPi-IIa expression in the BBM is reduced. In addition, it has been proposed that NHERF1 and NHERF2 are important for the coupling of PTH receptors (PTHR) to phospholipase C (PLC) and the activation of the protein kinase C (PKC) pathway. Here we tested the role of NHERF1 in the regulation of NaPi-IIa by PTH in NHERF1 deficient mice. Immunohistochemistry and Western blotting demonstrated that stimulation of apical and basolateral receptors with PTH 1-34 led to internalization of NaPi-IIa in wildtype and NHERF1 deficient mice. Stimulation of only apical receptors with PTH 3-34 failed to induce internalization in NHERF1 deficient mice. Expression and localization of apical PTHR were similar in both wildtype and NHERF1 deficient mice. Activation of the protein kinase C and A dependent pathways with DOG or 8-Br-cAMP induced normal internalization of NaPi-IIa in wildtype as well as in NHERF1 deficient mice. The stimulation of PLC activity due to apical PTHR was impaired in NHERF1 deficient mice. These data suggest that NHERF1 in the proximal tubule is important for PTH-induced internalization of NaPi-IIa and specifically couples the apical PTHR to PLC.