Familial Mediterranean fever (FMF) is a febrile disease characterized by acute, spontaneously resolving episodes of fever and pain caused by serosal inflammation and associated with mutations in the FMF gene, MEFV. Prophylaxis is maintained with colchicine. To our knowledge, no study has yet shown an association between FMF and cirrhosis of the liver. We conducted the current study to describe cryptogenic cirrhosis in FMF and to examine the possible relationship between the 2 entities. Patients with chronic liver disease were retrospectively identified through a computer search of a registry of 6000 patients with FMF followed in the clinics of the National Center for FMF. Data pertaining to FMF phenotype and genotype and characteristics of the liver disease were abstracted from patients' charts. Cryptogenic cause of cirrhosis was determined by exclusion of known causes of liver disease. Nine patients with cryptogenic cirrhosis were identified, comprising 0.15% of the FMF patient population, a rate significantly higher than the rate of 0.015% of cirrhosis of all types expected in the total population of Israel (p < 0.000). Most patients had typical FMF, with a normal severity score distribution. The mean daily dose of colchicine was 1.4 +/- 0.4 mg, not different from the usual dose. All 7 patients who underwent mutation analysis had 2 mutations. Five of them were homozygous for M694V. Child-Pugh classification was determined in 6 patients at the time of cirrhosis diagnosis, and was classified as A in 4 of them. These findings suggest that MEFV may serve as a modifier gene in cryptogenic cirrhosis. Genetic analysis in patients with cryptogenic cirrhosis unrelated to FMF, particularly patients of a Mediterranean origin, may be warranted in future studies.