Objective: Familial Mediterranean fever (FMF) is an autoinflammatory disease manifested as recurrent serosal inflammation. An association between FMF and malignancy has not been evaluated. The aim of this study was to estimate cancer risk in a large cohort of FMF patients from a single institution. Methods: The study cohort consisted of 8,534 FMF patients registered at the National FMF Center in Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and then stratified by age and sex. Standardized incidence ratios (SIRs) for cancers were calculated. Results: Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970–2011. The overall cancer risk among patients with FMF was significantly lower than was expected in specific sex and ethnic groups of the Israeli population: for males of Jewish ethnicity, SIR 0.66 (95% confidence interval [95% CI] 0.55–0.77), P < 0.001; for females of Jewish ethnicity, SIR 0.75 (95% CI 0.64–0.86), P < 0.001; and for males of Arab ethnicity, SIR 0.34 (95% CI 0.07–0.99), P = 0.024. Conclusion: FMF patients have a significantly lower incidence of cancer than the general population of Israel. This pattern was demonstrated in 2 ethnic populations: Jewish and Arab. We speculate that the lower cancer incidence could be attributed to a direct physiologic effect of FMF or to its treatment.