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Lycopene has been shown to be associated with anticancer effects in numerous tumor types. However, the underlying mechanisms of lycopene in human head and neck squamous cell carcinoma (HNSCC) remain to be determined. The present study aimed to investigate the involvement of lycopene overload and the cytotoxic effects of lycopene on HNSCC cells, and to determine the possible mechanisms involved. Treatment with lycopene at a dose of >10 μM for >24 h inhibited the growth of FaDu and Cal27 cells in a time- and dose-dependent manner. The clearest increase in growth inhibition was due to the apoptotic population being significantly increased. The invasion abilities decreased with 25 μM lycopene exerting significant inhibitory effects (P<0.01). Mechanistic studies revealed that lycopene induced the upregulation of the pro-apoptotic protein, B-cell lymphoma-associated X protein, and therefore, resulted in the inhibition of the protein kinase B and mitogen-activated protein kinase signaling pathway. These data provided insights into the antitumor activity of lycopene in HNSCC cells. [ABSTRACT FROM AUTHOR]