BACKGROUND: In patients with chronic hepatitis C (CHC), liver stiffness measurement (LSM) by transient elastography (TE), is closely related to the stage of fibrosis, but may be affected by necroinflammation. Other factors, such as insulin resistance (IR), might influence the performance of LSM. AIMS: To evaluate in a cohort of nondiabetic patients with genotype 1 CHC, whether IR and other anthropometric, biochemical, metabolic and histological factors contribute to LSM and to identify the best cut-off values of LSM for predicting different stages of fibrosis. METHODS: Nondiabetic patients with genotype 1 CHC (n = 156) were evaluated by liver biopsy (Metavir score), anthropometric, biochemical and metabolic features including IR. Furthermore, all subjects underwent LSM by TE. RESULTS: Severe fibrosis (F3-F4) was associated with LSM (OR 1.291; 95%CI 1.106-1.508). LSM was also independently correlated with low platelets (P = 0.03), high gammaGT (P or =8 KPa was identified as the best cut-off for predicting severe fibrosis (AUC 0.870); yet this cut-off still failed to rule out F3-F4 fibrosis in 22.7% of patients (false-negative rate) or rule in F3-F4 in 19.6% (false-positive rate). Platelets 2.7 were the major determinants of these diagnostic errors in predicting severe fibrosis. Conclusions In nondiabetic patients with genotype 1 CHC, insulin resistance, gammaGT and platelet levels contribute to LSM independently of liver fibrosis. The identification of these three factors contributes to a more correct interpretation of LSM.