Background & Aims: Most patients with extreme obesity have nonalcoholic fatty liver disease (NAFLD). Although gastric bypass (GBP) surgery is the most common bariatric operation performed in obese patients in the United States, the effect of GBP surgery-induced weight loss on the metabolic and hepatic abnormalities associated with NAFLD are not clear. Methods: Whole-body glucose, fatty acid and lipoprotein kinetics, liver histology, and hepatic cellular factors involved in inflammation and fibrogenesis were evaluated in 7 extremely obese subjects (body mass index, 58 ± 4 kg/m2) before and 1 year after GBP surgery. Results: At 1 year after surgery, subjects lost 29% ± 5% of initial body weight (P < .01); palmitate rate of appearance in plasma, an index of adipose tissue lipolysis, decreased by 47% ± 4% (P < .01); endogenous glucose production rate decreased by 27% ± 7% (P < .01); and very-low-density lipoprotein-triglyceride secretion rate decreased by 44% ± 9% (P < .05). In addition, GBP surgery-induced weight loss decreased hepatic steatosis but did not change standard histologic assessments of inflammation and fibrosis. However, there was a marked decrease in hepatic factors involved in regulating fibrogenesis (collagen-α1(I), transforming growth factor-β1, α-smooth muscle actin, and tissue inhibitor of metalloproteinase 1 expression and α-smooth muscle actin content) and inflammation (macrophage chemoattractant protein 1 and interleukin 8 expression) (P < .05, compared with values before weight loss). Conclusions: These data demonstrate that weight loss induced by GBP surgery normalizes the metabolic abnormalities involved in the pathogenesis and pathophysiology of NAFLD and decreases the hepatic expression of factors involved in the progression of liver inflammation and fibrosis.