We tested the power of tumor necrosis factor (TNF)-alpha and/or leptin in predicting the degree of liver involvement in children with nonalcoholic fatty liver disease (NAFLD). We measured serum levels of TNF-alpha and leptin and computed NAFLD activity score (NAS) (NAS >or= 5, diagnostic of nonalcoholic steatohepatitis [NASH]) in 72 consecutive biopsy-proven NAFLD cases (training and validation sets, 36 cases each). Univariate analysis evaluated variables significantly associated with a diagnostic NAS. Receiver operating characteristic (ROC) curve analysis assessed the diagnostic value of selected variables in predicting a NAS of 5 or more.TNF-alpha (P < .0001), leptin (P = .001); triglycerides (P = .013), and alkaline phosphatase (P = .046) levels were significantly associated with a NAS of 5 or more. TNF-alpha and leptin levels predicted the risk of NAS of 5 or more. ROC analyses defined cutoff values for TNF-alpha, leptin, and risk score. They identified 90%, 83%, and 83% of the cases, respectively, with a NAS of 5 or more (true-positive cases) from the validation set.TNF-alpha alone or combined with leptin in a simple risk score can accurately predict a NAS of 5 or more. TNF-alpha seems to be a specific laboratory marker of NASH.