Most people with hepatitis C virus (HCV) develop chronic infection with persistent viremia. Resolution of infection is associated with antiviral cellular immune responses of T helper 1 (Th1) type. Interleukin-12 (IL-12) is a key cytokine in the generation of Th1 responses, and functionally relevant polymorphisms of the IL12B gene and its promoter have been described recently. We sought an association between three IL12B polymorphisms and outcome of HCV infection in 195 HCV antibody-positive patients; 123 were chronically infected with detectable HCV RNA, and 72 had spontaneously resolved infection testing repeatedly negative for HCV RNA. Genotyping was performed for a single nucleotide polymorphism (SNP) in the 3'-UTR (1188A/C) of the IL12B gene and for 4-bp insertion/deletion polymorphisms in the IL12B promoter region and in the intron 4 region of the IL12B gene. We found chronically infected patients were significantly more likely than those with resolved HCV infection to be homozygous for the 3'-UTR A allele (66% vs. 50%; chi-square = 4.12, p = 0.04 with Yates correction), which has been associated with lower IL-12 production. No other significant association was found. Our findings support the concept that an individual's genetically determined ability to produce IL-12 is another factor that can influence the outcome of HCV infection.