Fanconi anemia (FA) rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). FA patients with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work we searched and validated two already approved drugs as new potential therapies for HNSCC in FA patients.We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify non-genotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety.Several FDA/EMA-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in FA HNSCC cell lines. The two best candidates gefitinib and afatinib, EGFR inhibitors approved for non-small-cell lung cancer (NSCLC), displayed non-tumor/tumor IC50 ratios of ~400 and ~100 times, respectively. Neither gefitinib nor afatinib activated the FA signaling pathway or induced chromosomal fragility in FA cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two FA patient-derived HNSCCs. Finally, in vivo toxicity studies in Fanca-deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side-effects, no toxicity to bone marrow progenitors and did not alter any hematological parameters.Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA approved anticancer drugs exerting cancer specific toxicity for HNSCC in FA patients.