Human T-cell leukemia virus (HTLV) type I-related endogenous sequences (HRES) have been cloned from a human genomic library. HRES-1/1 is present in DNA of all normal donors examined. By nucleotide sequence analysis, HRES-1/1 contains two potential open reading frames capable of encoding a p25 and a p15. A 684 bp flanking region 5' from the first ATG codon of p25 contains a TATA-box, a poly-adenylation signal, a putative tRNA primer binding site, and inverted repeats at locations which are typical of a retroviral long terminal repeat. Phylogenetic analysis suggests that HRES-1/1 entered the genome in primates, presumably as an exogenous retrovirus. From the deduced amino acid sequence of HRES-1/1 p25, residues 6-36 show a sequence homology of 32% and 39% to gag region segments of HTLV-I and HTLV-II, while residues 104-139 display a sequence homology of 33% and 28% to the gag regions of human immunodeficiency virus type 2 (HIV-2) and feline sarcoma virus (FSV), respectively. This suggests that the original exogenous virus infecting primate may be chimeric in structure. The HRES-1/1 genomic locus is transcriptionally active in lymphoid cells, melanoma cells, and embryonic tissues.