BACKGROUND: This study assessed the association of alanine-aminotransferase (ALT) and hepatitis C virus (HCV) RNA levels with pro-inflammatory and pro-fibrogenic cytokines and chemokines during acute HCV infection to provide further insight into the potential HCV immunopathogenesis. METHODS: Participants in the ATAHC study, a prospective study of recent HCV infection, with detectable HCV RNA at the time of HCV detection were included. Plasma levels of 27 cytokines and chemokines were measured and their correlation with ALT and HCV RNA levels were assessed. Log10 transformed cytokines and ALT values were used in the analysis. RESULTS: Among 117 individuals, the plasma levels of interferon-gamma inducible protein-10 (IP-10) and macrophage inflammatory protein-1beta (MIP-1beta) were positively correlated with ALT levels (IP-10: r = 0.42, P < 0.001; MIP-1beta: r = 0.29, P = 0.001) and HCV RNA levels (IP-10: rs = 0.44, P < 0.001; MIP-1beta: rs = 0.43, P < 0.001). Using linear regression, after adjusting for sex, age, infection duration, symptomatic infection, HIV co-infection, interferon-lambda rs12979860 genotype, HCV genotype, and assay run, higher ALT levels (beta = 0.20; 95 % CI: 0.07, 0.32; P = 0.002) and HCV RNA levels >400,000 IU/mL (vs. <8,500 IU/mL; beta = 0.16; 95 % CI: 0.03, 0.28; P = 0.014) were independently associated with higher IP-10 levels. HCV RNA levels >400,000 IU/mL (vs. <8,500 IU/mL; beta = 0.16; 95 % CI: 0.01, 0.31; P = 0.036) were associated with higher MIP-1beta levels. CONCLUSIONS: During acute HCV infection, high ALT and HCV RNA levels were associated with increased IP-10 levels, while high HCV RNA levels were also associated with increased MIP-1beta levels. These data suggest that IP-10 and MIP-1beta may have a role in HCV immuno-pathogenesis starting early in acute HCV infection.