Macrophages are involved in inflammation and liver fibrosis and soluble (s)CD163 is a specific marker of activated macrophages. We investigated associations between sCD163 and biochemical and histological parameters of inflammatory activity and fibrosis in 551 patients with chronic hepatitis C virus (HCV) and 203 patients with chronic hepatitis B virus (HBV) before antiviral treatment. Scheuer histological scores of activity and fibrosis were obtained. Clinical, biochemical, and metabolic parameters were recorded. We measured sCD163 by enzyme‐linked immunosorbent assay (ELISA). Soluble CD163 was higher in patients with HCV compared to HBV (3.6 [interquartile range (IQR) 2.5‐5.4] versus 2.4 [IQR 1.8‐3.6] mg/L, P < 0.001). sCD163 was associated with fibrosis stages for both HCV (odds ratio [OR] 1.49, 95% confidence interval [CI]: 1.38‐1.61) and HBV (OR 1.32, 95% CI: 1.17‐1.49) patients, with highest levels in patients with advanced fibrosis and cirrhosis. sCD163 was a marker of fibrosis independent of other biochemical parameters and known risk factors. We created two novel sCD163‐based fibrosis scores, CD163‐HCV‐FS and CD163‐HBV‐FS, which showed areas under the receiver operating characteristics curve (AUROC) of 0.79 (95% CI: 0.74‐0.83) and 0.71 (95% CI: 0.62‐0.79), respectively, for significant fibrosis. Compared to existing fibrosis scores, CD163‐HCV‐FS was significantly superior to the aspartate aminotransferase (AST) to platelet ratio index (APRI) for all fibrosis stages and to FIB‐4 for significant fibrosis, but CD163‐HBV‐FS was not. Conclusion: sCD163 levels are increased in patients with chronic viral hepatitis, reflecting macrophage activation. Increased sCD163 is associated with the severity of disease and predicts fibrosis. A sCD163‐based fibrosis score, CD163‐HCV‐FS, is superior to APRI and FIB‐4 for the diagnosis of significant fibrosis in patients with HCV infection. (Hepatology 2014;60:521–530)