In a search for glucocorticoid attenuated response genes (GARGs) induced by lipopolysaccharide (LPS) in murine Swiss 3T3 cells, we cloned 12 GARG cDNAs (J. B. Smith and H. R. Herschman, 1995, J. Biol. Chem. 270, 16756-16765). Analysis of complete cDNA sequences indicates that three of these genes encode members of a highly conserved family of proteins containing multiple tetratricopeptide repeat (TPR) domains. GARG-16 is a homologue of the interferon-induced human IFI-56K gene. GARG-39 is a homologue of the interferon-induced human ISG-54K and hamster CL-54K genes. The predicted GARG-49/IRG2 protein is 60-75 amino acids shorter than other known members of this gene family, and its carboxyl-terminal half is relatively divergent. Homologues of GARG-49/IRG2 in other species have not been reported. The predicted GARG-16 and GARG-39 proteins, and their homologues, contain 10 TPR domains. GARG-49/IRG2 shares the first 6 domains and part of the 7th, but lacks domains 8,9, and 10. Message levels of GARG-16, GARG-39, and GARG-49/IRG2 are increased by LPS stimulation in Swiss 3T3 cells and in peritoneal macrophages. Unlike many primary response genes, these three genes are not induced by serum stimulation in Swiss 3T3 cells. All three are induced in the RAW 264.7 macrophage cell line by LPS, by interferons-alpha/beta, and by interferon-gamma. Despite these similarities, quantitative differences in their responses to different stimuli indicate that GARG-16, GARG-39, and GARG-49/IRG2 are regulated independently. We speculate that the proteins encoded by these LPS- and interferon-inducible genes may participate in multicomponent assemblies via their TPR domains.