Interferon-gamma (IFN-gamma) is an important cytokine that regulates cellular immune responses to intracellular pathogens and neoplasia. Regulation of IFN-gamma expression is stringently controlled at the transcriptional level. In this report we describe two novel single nucleotide polymorphisms (SNPs); one, at -179 in the promoter, occurs in 4% of African Americans. This SNP represents a guanidine to thymidine transition and creates a potential AP-1 binding element. Electrophoretic mobility shift analysis reveals a unique complex binding to an oligonucleotide containing the variant -179T but not to the -179G using nuclear extracts from human peripheral blood T cells. In reporter gene assays, T cell lines transfected with the variant -204(179T) IFN-gamma promoter show a six to 13-fold induction of luciferase activity in response to TNF-alpha over the common -204(179G) construct. The -179T allele identified in the proximal IFN-gamma promoter confers TNF-alpha inducibility and may prove important in human immune disorders and responsiveness to pathogens.