Renal tubular cyst formation and progressive enlargement in autosomal recessive polycystic kidney disease (ARPKD) are mediated by increased epithelial cell proliferation and altered transtubular fluid transport. Epidermal growth factor (EGF)-like peptides have been proposed to play roles in normal nephrogenesis and cystic tubular mitogenesis. Therefore, renal expression of EGF receptor (EGFR) protein and mRNA was examined in an animal model for ARPKD, the C57BL/6Jcpk/cpk (CPK) mouse. Both quantitative and qualitative abnormalities of EGFR expression were demonstrated. While both control and cystic proximal tubules, as well as control collecting tubules, demonstrated exclusive basalateral EGFR protein expression, cystic collecting tubules exhibited significant apical-lateral receptor localization. During nephrogenesis, EGFR protein expression was elevated in CPK renal tissue when compared to developmentally staged controls. Control and CPK kidneys expressed the same species of EGFR mRNA. Levels increased with developmental age, but were significantly higher at each stage of development in CPK kidneys. Overexpression of both EGFR protein and mRNA in CPK mice suggests altered control of EGFR protein and/or gene expression. EGFR mislocalization and overexpression may be mechanisms whereby the EGF-like factors in cyst fluid stimulate cystogenesis through an autocrine-paracrine cycle in ARPKD.