Previously, we demonstrated that the mammalian polo-like kinase (PLK), which participates in the regulation of the cell cycle, is a novel marker of cellular proliferation. Because current prognostic tools for the evaluation of patients with head and neck squamous cell cancer (HNSCC) need to be improved, we analyzed 89 patients and found elevated PLK expression in most tumors. Nodal stage as a crucial prognostic factor in HNSCC also correlated to PLK transcript levels (P = 0.0043). A Kaplan-Meier analysis showed that HNSCC patients with moderate versus high PLK expression survived significantly longer (5-year survival rates, 43% versus 12%; P = 0.0047). Interestingly, a combination of nodal stage and PLK expression contributed to discriminate patients with a better prognosis in the pN_0/1 and pN_2/3 groups, which could improve the definition of a suitable therapy.