Background/Aims: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC. Methods: The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction. Results: Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare. Conclusion: Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study.