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Background Cytotoxic T lymphocyte-associated factor 4 ( CTLA-4) functions as a negative regulator of T cell-mediated immune response. Molecular changes associated to CTLA-4 gene polymorphisms could reduce its ability to suppress and control lymphocyte proliferation. Aims To evaluate the frequency of CTLA-4 gene polymorphisms in chronic hepatitis C virus ( HCV) infected patients and correlate to clinical and histological findings. Methods We evaluated 112 HCV-infected subjects prospectively selected and 183 healthy controls. Clinical and liver histological data were analysed. −318C > T, A49G and CT60 CTLA-4 single -nucleotide polymorphisms ( SNPs) were studied by PCR- RFLP and AT(n) polymorphism by DNA fragment analysis by capillary electrophoresis in automatic sequencer. Results Eight AT repetitions in 3′UTR region were more frequent in HCV-infected subjects. We found a positive association of −318C and + 49G with HCV genotype 3 ( P = 0.008, OR 9.13, P = 0.004, OR 2.49 respectively) and an inverse association of both alleles with HCV genotype 1 ( P = 0.020, OR 0.19, P = 0.002, OR 0.38 respectively). Allele + 49G was also associated to aminotransferases quotients > 3 ( qALT, P = 0.034, qAST, P = 0.041). Allele G of CT60 SNP was also associated with qAST > 3 ( P = 0.012). Increased number of AT repetitions was positively associated to severe necroinflammatory activity scores in liver biopsies ( P = 0.045, OR 4.62). Conclusion CTLA-4 gene polymorphisms were associated to HCV-infection. Eight AT repetitions were more prevalent in HCV-infected subjects. −318C and + 49G alleles were associated to genotypes 1 and 3 infections and increased number of AT repetitions in 3′ UTR region favoured severe necroinflammatory activity scores in liver biopsies. [ABSTRACT FROM AUTHOR]