It is unknown whether transforming growth factor β1 (TGF‐β1) signaling uniformly participates in fibrogenic chronic liver diseases, irrespective of the underlying origin, or if other cytokines such as interleukin (IL)‐13 share in fibrogenesis (e.g., due to regulatory effects on type I pro‐collagen expression). TGF‐β1 signaling events were scored in 396 liver tissue samples from patients with diverse chronic liver diseases, including hepatitis B virus (HBV), hepatitis C virus (HCV), Schistosoma japonicum infection, and steatosis/steatohepatitis. Phospho‐Smad2 staining correlated significantly with fibrotic stage in patients with HBV infection (n = 112, P < 0.001) and steatosis/steatohepatitis (n = 120, P < 0.01), but not in patients with HCV infection (n = 77, P > 0.05). In tissue with HBx protein expression, phospho‐Smad2 was detectable, suggesting a functional link between viral protein expression and TGF‐β1 signaling. For IL‐13, immunostaining correlated with fibrotic stage in patients with HCV infection and steatosis/steatohepatitis. IL‐13 protein was more abundant in liver tissue lysates from three HCV patients compared with controls, as were IL‐13 serum levels in 68 patients with chronic HCV infection compared with 20 healthy volunteers (72.87 ± 26.38 versus 45.41 ± 3.73, P < 0.001). Immunohistochemistry results suggest that IL‐13–mediated liver fibrogenesis may take place in the absence of phospho–signal transducer and activator of transcription protein 6 signaling. In a subgroup of patients with advanced liver fibrosis (stage ≥3), neither TGF‐β nor IL‐13 signaling was detectable. Conclusion: Depending on the cause of liver damage, a predominance of TGF‐β or IL‐13 signaling is found. TGF‐β1 predominance is detected in HBV‐related liver fibrogenesis and IL‐13 predominance in chronic HCV infection. In some instances, the underlying fibrogenic mediator remains enigmatic. (HEPATOLOGY 2009.)