Cystic fibrosis liver disease (CFLD), which results from progressive hepatobiliary fibrosis, is an important cause of morbidity and mortality, but it is difficult to identify before portal hypertension (PHT) ensues. Clinical signs, serum alanine aminotransferase (ALT) levels, and ultrasound (US) are widely applied, but their value in predicting the presence of cirrhosis, the development of PHT, or adverse outcomes is undetermined. The potential gold standard, liver biopsy, is not standard practice and, notwithstanding sampling error considerations, has not been systematically evaluated. Forty patients with cystic fibrosis (median age 5 10.6 years) with abnormal clinical, biochemical, and US findings were subjected to dual-pass percutaneous liver biopsy. Clinical outcomes were recorded over 12 years of follow-up (median 5 9.5 years for survivors). Logistic regression and receiver operating characteristic analyses were applied to predict hepatic fibrosis (which was assessed by fibrosis staging and quantitative immunohistochemistry) and the occurrence of PHT. PHT occurred in 17 of 40 patients (42%), including 6 of 7 (17%) who died during follow-up. Clinical examination, serum ALT levels, and US findings failed to predict either the presence of liver fibrosis or the development of PHT. Fibrosis staging on liver biopsy, where the accuracy was improved by dual passes (P 5 0.002, nonconcordance 5 38%), predicted the development of PHT (P < 0.001), which occurred more frequently and at a younger age in those with severe fibrosis. Conclusion: Clinical modalities currently employed to evaluate suspected CFLD help to identify a cohort of children at risk for liver disease and adverse outcomes but do not predict an individual's risk of liver fibrosis or PHT development. Liver fibrosis on biopsy predicts the development of clinically significant liver disease. Dual passes help to address sampling concerns. Liver biopsy has a relevant role in the management of patients with suspected CFLD and deserves more widespread application. (HEPATOLOGY 2011;53:193-201) H epatobiliary fibrosis causes significant mortality and morbidity in patients with cystic fibrosis (CF). 1 Liver cirrhosis has been reported in up to 10% of children 2 and in less than 2% of adults with CF 3 ; suggesting a survival disadvantage. Liver disease is reportedly the third leading direct cause of death. 3 Complications such as portal hypertension (PHT), nutritional growth failure, and, in some cases, liver syn-thetic failure impair the quality of life in up to 20% of patients 1,4 ; this is also highlighted by improvements in the quality of life, nutritional status, and respiratory function after successful liver transplantation. 1,4 Cystic fibrosis liver disease (CFLD) has its origins early in life, 1,4 and its onset and progression to cirrhosis and PHT are unpredictable. Early diagnosis is elusive, 1,2,4 and a rigorous comparison of current diagnostic