To evaluate the prognostic significance of cyclin D1 protein/gene expressions in human head-and-neck squamous-cell carcinoma (HNSCC), we examined amplification of the cyclin-D1 gene (CCND1) by the differential PCR method and over-expression of cyclin-D1 protein by immunohistochemistry in 45 paraffin-embedded sections from HNSCC. Amplification of CCND1 was found in 10 (22%) cases and over-expression of cyclin D1 was found in 24 (53%) cases. CCND1 amplification was also found in 3 (25%) of 12 cases of dysplastic lesions adjacent to HNSCC. The overall 5-year survival of patients with CCND1 amplification or with protein over-production was significantly lower than that of patients without (p < 0.0001 and p < 0.05, respectively). However, with multivariate analysis, only amplification of CCND1 retained an independent prognostic value (p = 0.0018). These suggest that CCND1 amplification occurs at early stages of HNSCC tumorigenesis and is a more useful prognostic factor than over-expression of cyclin D1 in HNSCC.