Ubiquitin cross-reactive protein (UCRP) is an interferon-inducible ubiquitin homologue which is constitutively present in cells and can be conjugated to other proteins. Using a characterized polyclonal antiserum to UCRP, immunohistochemical localization of UCRP was performed on paraffin-processed normal human tissues and in human tissues known to contain ubiquitinated intracellular inclusions. The antibody to UCRP immunostained lymphoid cells, striated and smooth muscle, several epithelia, and neurons. The level of staining varied greatly between tissues but was in a consistent punctate pattern. Localization to neuromuscular junctions and striations is similar to that described for antisera to ubiquitin-protein conjugates. Inclusion bodies characterized by immunoreactivity to anti-ubiquitin were not detected by the antibody to UCRP. Importantly, because UCRP may also be detected by antisera to conjugated ubiquitin, future studies on the distribution of ubiquitin in tissue sections must now take account of possible cross-reactivity with UCRP.