Several host genetic factors play an important role in susceptibility to human immunodeficiency virus type 1 (HIV-1) infection and in its progression to acquired immune deficiency syndrome (AIDS). The interleukin-18 (IL-18) is a multifunctional proinflammatory cytokine that regulates immune responses and plays a pathogenic role in HIV-1 infection by enhancing viral replication. Single nucleotide polymorphisms (SNPs) in the IL-18 gene promoter region may lead to altered transcriptional activity and IL-18 production, and may account for variation in the risk of HIV-1 infection. We have investigated the association between IL-18 promoter polymorphism -607C>A and HIV-1 infection through a case-control study of 500 patients with HIV-1/AIDS and an equal number of age and sex matched controls in a north Indian population. Genotyping using sequence specific primer-polymerase chain reaction (SSP-PCR) showed a statistically significant reduced risk of HIV-1 infection for the A>A genotype [odds ratio (OR) = 0.57, 95% confidence interval (95% CI) = 0.33-0.98, p = 0.040], but not for the C>A genotype (OR = 0.87, 95% CI = 0.66-1.14, p = 0.321). We concluded that the -607A allele of the IL-18 gene promoter polymorphism may play a protective role against the progression of HIV-1 infection in this population.