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Here we establish monoclonal antibodies (mAbs) for detecting P1 and P2 promoter\u2010driven HNF4\u03b1, and evaluate their expression in normal adult human tissues and surgically resected carcinomas of different origins. Using immunohistochemical analysis, we demonstrate that, while P1 promoter\u2010driven HNF4\u03b1 is expressed in hepatocytes, small intestine, colon, kidney and epididymis, P2 promoter\u2010driven HNF4\u03b1 is expressed in bile duct, pancreas, stomach, small intestine, colon and epididymis. Altered expression patterns of P1 and P2 promoter\u2010driven HNF4\u03b1 were observed in gastric, hepatocellular and colorectal carcinomas. HNF4\u03b1 was expressed in lung metastases from renal cell, hepatocellular and colorectal carcinoma but was not observed in lung tumours. The P1 and P2 promoter\u2010driven HNF4\u03b1 expression pattern of tumour metastases correlated with the primary site of origin. P1 promoter\u2010driven HNF4\u03b1 was also found in intestinal metaplasia of the stomach. These data provide evidence for the tissue distribution of P1 and P2 promoter\u2010driven HNF4\u03b1 at the protein level and suggest that HNF4\u03b1 may be a novel diagnostic marker for metastases of unknown primary. We propose that the dysregulation of alternative promoter usage of HNF4\u03b1 is associated with the pathogenesis of certain cancers. Copyright \u00a9 2006 Pathological Society of Great Britain and Ireland. 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