Inducible nitric oxide synthase ( iNOS) is an important molecule involved in the host defense against infectious agents. iNOS is encoded by the NOS2A gene and well-defined haplotypes exist with respect to this gene. We examined whether these haplotypes were associated with the outcome of hepatitis C virus (HCV) infection in 619 Caucasian patients from seven European liver centres. We observed five major haplotypes: ( - 277A) +( - 1026G) +( - 1659C): haplotype 1; ( - 277G) +( - 1026T) +( - 1659C): haplotype 2; ( - 277G) +( -1026G)+(- 1659C): haplotype 3; (-277G)+(-1026T)+(-1659T): haplotype 4; and (-277A)+( -1026T)+(-1659C): haplotype 5. Distributions of these haplotypes are comparable with those of previous studies. Homozygotes for haplotype 2 or those with haplotypes 2/4 were more likely than those with the 1/1 (wild type) combination to have self-limiting infections (odds ratios (OR) = 3.43; 95% confidence intervals (95% CI): 1.10 - 8.0; P = 0.0206 and OR = 5.15; 95% CI: 1.32 - 14.32; P = 0.0018, respectively). Conversely, carriage of haplotype 1 was associated with the lack of self-limiting disease ( OR = 0.48; 95% CI: 0.27 - 0.83; P = 0.009). The effect was mainly among males ( OR = 0.41; 95% CI: 0.182 - 0.942; P = 0.031 for males, and OR = 0.55; 95% CI: 0.24 - 1.37; P = 0.136 for women). Carriage of haplotype 1 was not associated with initial response ( P = 0.268) or sustained response (P>0.171). Combinations of haplotypes 1/4 were more likely to respond to interferon monotherapy in comparison of initial responders to nonresponders ( OR = 2.25; 95% CI: 1.05 - 5.68; P = 0.0275).