We have investigated the DNase I hypersensitivity of a hybrid mouse/human beta-globin gene in erythroid and non-erythroid cells of transgenic mice, to examine the relationship between the chromatin structure and the expression of an exogenous gene. The hybrid globin gene was previously shown to be expressed specifically in erythroid cells in some transgenic lines. The maximal level of hybrid globin mRNA accumulation was a few percent of the endogenous level, and we show here that this results from a low rate of transcription. In erythroid cells from two transgenic lines in which the hybrid gene is expressed, we detect a set of DNase I hypersensitive sites whose locations are indistinguishable from those in endogenous beta-globin genes. The hybrid globin gene contains no DNase I hypersensitive sites in transgenic mouse brain cells. Thus, the tissue-specific expression of the exogenous globin gene is reflected in, and perhaps mediated by, tissue-specific changes in chromatin structure.