We have used the monoclonal antibody IFNaR3 that recognizes the alpha subunit of the type I interferon (IFN) receptor to study the expression of this receptor in a large series of normal human adult and fetal tissues, as well as in a large number of tumors of diverse origin. Among fetal tissues (8-20 weeks) the type I IFN receptor was expressed in liver, striated muscle, epidermis, renal tubules, choroid plexus of the CNS, and epithelia of different origins (bronchial, gastrointestinal, and pancreatic). Adult tissues showed a similar pattern that includes epithelia from salivary ducts, genital tract, bladder, breast, as well as germinal centers of lymph nodes, tonsils, and spleen. The study of a large series of tumors revealed that the type I IFN receptor is expressed in most, but not all, melanomas, bladder, kidney, small bowel, lung, and breast adenocarcinomas. The majority of lymphomas, sarcomas, and endocrine tumors proved negative. These results support the concept that the type I IFN receptor is rather ubiquitously expressed in normal and malignant epithelial tissues. More interestingly, the expression of the type I IFN receptor was not detected in all tumors, raising the question of whether some cases may fail IFN alpha therapy due to the lack of receptor expression. This report demonstrates that the IFNaR3 monoclonal antibody can be used for receptor detection in paraffin-embedded sections and it could represent a useful tool in the search for correlations between IFN alpha response and receptor expression in different diseases.