Interleukin-18 is a proinflammatory cytokine, which strongly induces IFN-gamma production. We have cloned the human IL-18 promoter and screened for possible polymorphisms. Three single nucleotide polymorphisms were detected in the promoter and two polymorphisms in the 5'-nontranslated region of the gene. Three combinations of these polymorphisms were observed in the Swedish population. All IL-18 promoter alleles were found to have clear promoter activity when inserted into a luciferase reporter vector. There were no significant differences in promoter activity between alleles without stimulation, but after stimulation with PMA/ionomicin one of the alleles had clearly lower activity than the other (P<0.01). Measurement of IL-18 and IFN-gamma production in 48 multiple sclerosis patients by RT-PCR showed slightly higher expression of IL-18 in individuals homozygous for the most frequent haplotype. Two IL-18 promoter polymorphisms were analyzed by sequence specific PCR in 208 multiple sclerosis patients and 139 healthy controls, however, no significant differences were found. In summary, our data indicate that common IL-18 promoter polymorphisms influence the expression of IL-18 and potentially also of IFN-gamma.