Head and neck cancers are commonly treated with the DNA-damaging agent cisplatin. While many tumors respond well to cisplatin treatment, some do not. The mechanism for this differential sensitivity of head and neck tumors to cisplatin is not understood in detail. In this study, we explored whether the functional status of the Fanconi anemia and BRCA pathway (FA/BRCA) would predict cisplatin sensitivity in head and neck cancer cells. The FA/BRCA pathway is critical for the orchestration of the cellular response to cisplatin and other DNA cross-linking agents. It was found that three out of four cisplatin-sensitive head and neck cancer cell lines showed defective formation of FANCD2 nuclear foci while all four cisplatin-resistant cell lines tested were proficient in FANCD2 foci formation following cisplatin treatment. The defect in FANCD2 foci formation in the cisplatin-sensitive cell lines was not due to defective monoubiquitylation of FANCD2 but appeared to be due to reduced expression or defective function of BRCA1 since expression of exogenous BRCA1 restored the ability of these cells to induce FANCD2 foci following cisplatin treatment and enhanced cisplatin resistance. These results suggest a possible role for BRCA1 in modulating cisplatin sensitivity in head and neck cancer cells.