The gene PKD I, which is mutated in type I autosomal dominant polycystic kidney disease (ADPKD 1), encodes a large protein of novel structure and unknown function and distribution that has been named polycystin. To gain better insight into polycystin function, we raised a panel of antisera against synthetic peptide antigens derived from the unique portion of the predicted polycystin sequence. Antisera were used to immunolocalize the protein in a variety of normal human fetal, childhood, and adult tissues as well as kidney and liver tissue from individuals with ADPKD 1, the genetically distinct ADPKD 2, and acquired renal cystic disease (ARCD). Subcellular localization studies were carried out on human cultured cell lines of renal epithelial origin. In normal tissues, polycystin expression was noted in renal tubular epithelial cells from 20 weeks gestation to 4 years postpartum, and in hepatocytes and biliary epithelium up to 4 years, but not in adult kidney or liver. Expression also was present in fetal and childhood pancreas, myocardium, bowel, and adrenal medulla. In cell lines of renal epithelial origin, immunofluorescence and immunoelectron-microscopical studies showed localization of polycystin epitopes to the peripheral cytoplasm. Kidney and liver from four unrelated adults with known ADPKD 1 showed strong staining, which was not seen in kidney and liver from one adult with ADPKD 2 or in kidney from three patients with ARCD. We conclude that polycystin is expressed in renal tubular epithelial cells as well as a variety of other cell types during development and growth but is absent or weakly expressed in adult kidney and liver. Overexpression of polycystin epitopes within affected tissue may be a specific feature of some or all cases of ADPKD 1.