Progressive human renal cystic diseases are characterized by proliferation of the epithelial cells lining the cyst. The kidney synthesizes epidermal growth factor and its presence in renal cyst fluid might contribute to renal epithelial cell proliferation. We screened autosomal dominant polycystic kidney disease, acquired renal cystic disease, the von Hippel-Lindau syndrome, multilocular cystic nephroma, multicystic dysplastic kidney disease and simple cyst fluids for the presence of epidermal growth factor by radioreceptor assay, specific radioimmunoassay, immunoprecipitation and immunoblotting. Multiple epidermal growth factor immunoreactive species of approximately 180 kD. and lower molecular weights were present in almost all cyst fluids examined, suggesting endogenous synthesis and limited proteolysis of epidermal growth factor precursor protein in cyst fluid. Tamm-Horsfall protein was detected by enzyme-linked immunosorbent assay in most cysts (for example 55 of 59 autosomal dominant polycystic kidney disease samples). The majority of simple and autosomal dominant polycystic kidney disease renal cysts contained high sodium ion concentration, epidermal growth factor precursor protein and Tamm-Horsfall protein, characteristic of the early thick ascending limb. Rather than the mere presence of epidermal growth factor in renal cyst fluids, increased sensitivity to epidermal growth factor or other mitogens present in renal cyst fluid may be pathogenic in progressive renal cystic disease.