The His-1 gene is expressed as a 3-kb spliced and polyadenylated RNA that is believed to function in the absence of an encoded protein. The precise function of the His-1 gene is unknown, but its transcriptional activation in a series of mouse leukemias has implicated the His-1 RNA in leukemogenesis when it is abnormally expressed. To study the oncogenic potential of this gene in more detail, we have examined the normal tissue distribution of His-1 RNA during mouse embryogenesis and in various adult tissues. His-1 expression was detected at low levels in the epithelia of the adult mouse stomach, prostate, seminal vesicle, and the developing choroid plexus by in situ hybridization. All other tissues examined lacked detectable levels of hybridizing RNA, suggesting that normal His-1 gene expression is highly restricted to these epithelial sites. These transcripts were not detectable by Northern blot analysis of normal tissues but were readily identified in five mouse leukemias and in five carcinomas of the choroid plexus. These data indicate that the His-1 gene expression is highly restricted and suggest that inappropriate activation of this gene may contribute to carcinogenesis.