Three functional members of the 1–8 gene family have been isolated on a single human genomic DNA fragment of less than 18 kb. The 1–8U and 1–8D genes are extremely similar: each is contained within a <2‐kb fragment, has in its 5′flanking region two adjacent 14‐base‐pair sequences showing high similarity to interferon‐stimulable response elements (ISREs) and has two highly related exons. The third gene (9–27) has a similar overall structure, shows substantial similarity to the 1–8s but has only one ISRE which is 3′ of two CCAAT boxes not present in the 1–8U and D genes. The cDNAs corresponding to the three genes share 120 nucleotides of identical sequence and show > 90% identity over 70% of the coding sequence. For the 1–8U and D genes the high similarity extends into the 5′ non‐coding and flanking regions. The open reading frames encode polypeptides that are likely to be of very similar structure. Antiserum to a conserved peptide detects a polypeptide(s) of about 14 kDa on PAGE which separates into three components on isoelectric focussing. The 9–27 and 1–8U genes are highly interferon‐inducible, the 1–8D gene is much less so. These differences are mimicked by the activities of the corresponding ISREs placed 5′ of a marker gene in expression constructs. They presumably reflect differences in the interaction of the ISREs with the various interferon‐inducible and constitutive factors that govern the interferon response.