Serial liver biopsies are the gold standard by which the progression of fibrosis is evaluated. This longitudinal cohort study assessed the different rates in the progression of fibrosis using serial liver biopsies and serum fibrosis markers YKL-40 and PIIINP and the cytokines, transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNuF-alpha). A 10-year cohort study was performed in patients with hepatitis C virus (HCV) alone or HCV and schistosomiasis. Patients were enrolled at the time of acute HCV infection and prospectively evaluated with two liver biopsies (at entry and end of follow-up), and true rates in the progression of fibrosis were calculated per year. Serum YKL-40, N-terminal propeptide of collagen III (PIIINP), TGF-beta, and TNF-alpha were measured, as well as the expression of TGF-beta, TNF-alpha, and YKL-40 mRNA in liver tissue. A significant increase in the progression rates of fibrosis occurred in the coinfected group (0.61 +/- 0.13) compared with the HCV monoinfection group (0.1 +/- 0.06; P < .001)). The progression of fibrosis rate/year had a direct linear correlation for YKL-40 (r = 0.892, P < .001) and for PIIINP (r = 0.577, P < .01). YKL-40 showed a linear correlation with TGF-beta (r = 0.897, P < .001). Hepatic mRNA levels of YKL-40 and TGF-beta correlated with the serum levels, confirming a hepatic source for the elevated serum levels. In conclusion, serial cytokine and fibrosis markers can accurately determine the rate at which fibrosis is progressing, identifying both those with rapid fibrosis and those with stable disease.