Epidemiological data have indicated a close relationship between chronic HCV infection and non-Hodgkin's B-cell lymphoma (B-NHL). In this study, functional phenotypes and gene expression profiles of PBMCs were analyzed in chronic hepatitis C (CHC) patients who developed B-NHL. The frequencies of effector CD8(+) T cells and cytotoxic natural killer cells increased in CHC patients with B-NHL compared to those in CHC patients without B-NHL. These phenotypic changes may reflect the host's immune response to neoplasia. The mRNA expression levels of several oncogenes increased in CHC patients without B-NHL, but were much higher in CHC patients with B-NHL, while mRNA levels of type I IFNs were decreased in CHC patients without B-NHL and were nearly negligible in CHC patients with B-NHL. Interestingly, the mRNA expression levels of activation-induced cytidine deaminase and caspase recruitment domain-containing proteins markedly increased in CHC patients without B-NHL but decreased in CHC patients with B-NHL. These results are discussed in view of the possible involvement of HCV infection in B-cell lymphomagenesis.