We have described previously a variable length CA repeat sequence in the first intron of the human IFN-gamma gene and showed that allele #2 is associated with high in vitro IFN-gamma production. In a consecutive study, allele #2 was found to be associated with allograft fibrosis in lung transplant patients, confirming its role as a marker of high IFN-gamma production, both in vivo and in vitro. In this study we have sequenced 50 PCR products that had been typed previously by PAGE for the identification of CA microsatellite alleles. We report on a novel single nucleotide polymorphism, T to A, at the 5' end of the CA repeat region in the first intron of the human IFN-gamma gene (+874*T/A). There is an absolute correlation between the presence of T allele and the presence of the high-producing microsatellite allele #2. This T to A polymorphism coincides with a putative NF-kappa B binding site which might have functional consequences for the transcription of the human IFN-gamma gene. Therefore, the T to A polymorphism could directly influence the level of IFN-gamma production associated with the CA microsatellite marker.