Obesity and fatty liver are commonly observed among patients with chronic hepatitis C virus (HCV) and are risk factors for increased hepatic fibrosis. Obesity is accompanied by a low-grade, chronic inflammatory response that may contribute to pathogenesis of obesityrelated comorbidities. To assess whether obesity and steatosis potentiate expression of inflammatory markers in chronic HCV, serum protein and hepatic messenger RNA (mRNA) levels of c-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-โฃ) were measured in 171 patients with chronic HCV. The relationships of body mass index, steatosis, histological features of inflammation and fibrosis with serum and hepatic levels of these factors were determined. In comparison with lean patients, overweight and obese subjects had increased circulating (P < 0.001) and hepatic (P โซุโฌ 0.003) CRP, and there was a significant correlation between serum protein and hepatic CRP mRNA levels (r s โซุโฌ 0.51, P < 0.001). Obesity (P โซุโฌ 0.001) and steatosis (P < 0.001) were associated with increased circulating but not hepatic IL-6, and a weak correlation was seen between serum protein and hepatic IL-6 mRNA levels (r s โซุโฌ 0.29, P โซุโฌ 0.003). An independent relationship was seen between hepatic TNF-โฃ mRNA levels and higher total inflammatory score (P < 0.001) and stage of fibrosis (P โซุโฌ 0.037). Subjects with HCV genotype 3 had lower hepatic TNF-โฃ mRNA levels compared with subjects with genotype 1 (P โซุโฌ 0.017), but there was no relationship between serum TNF-โฃ protein and hepatic TNF-โฃ mRNA levels. Conclusion: In patients with chronic HCV, obesity and steatosis are associated with increased expression of selected inflammatory markers; however, circulating levels of IL-6 and TNF-โฃ do not reflect hepatic expression. Hepatic TNF-โฃ was associated with both increased inflammatory activity and hepatic fibrosis, providing support for the key role of this pro-inflammatory cytokine in liver injury in chronic HCV. (HEPATOLOGY 2008;48:80-87.) O besity is often accompanied by activation of pro-inflammatory signaling pathways that lead to production of biochemical markers and mediators of inflammation. 1 In obese subjects, this lowgrade, chronic inflammatory response is indicated by increased plasma levels of c-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-โฃ) and other acute phase reactants. In comparison with lean controls, adipose tissue from obese subjects and rodent models of obesity has increased expression of various inflammatory mediators and cytokines. These factors are produced by adipocytes and by macrophages infiltrating adipose tissue. In addition, rodent models of obesity are accompanied by increased hepatic expression of pro-inflammatory cytokines, including IL-6 and TNF-โฃ. Accumulating data suggest that this inflammatory response has a causal relationship with obesity-related comorbidities such as insulin resistance 3 and cardiovascular disease. It has also been postulated that the increased production of pro-inflammatory cytokines may have a