Background. Patients with head and neck squamous cell carcinoma (HNSCC) have an unfavorable prognosis, with a 5-year survival rate of approximately 40%. Genetic analyses have revealed that the majority of HNSCC carry complex, aneuploid karyotypes, showing numerical and structural chromosomal imbalances. New compounds are being developed that target chromosomal instability in general, specifically affecting cells with aneuploid karyotypes. Methods. Two of such compounds, AICAR (5-aminoimidazole-4-carboxamide riboside) and 17-AAG (17-allylamino-17-demethoxygeldanamycin), were tested using a panel of stable diploid and unstable aneuploid HNSCC cell lines, and short-term cultures of normal keratinocytes as control. Results. A significant growth inhibitory effect by both compounds was observed in the aneuploid compared to diploid HNSCC cell lines and to the normal keratinocytes. This effect was independent from the TP53 mutation status. Combination treatment with AICAR and 17-AAG demonstrated the strongest inhibition. Conclusions. Aneuploidy-targeted therapy may be a viable addition to the treatment options for HNSCC. Head Neck, 2014.