Altered Cyclin D1 activity, due to gene amplification and/or protein overexpression, is related to the development of several human cancers, including head and neck SCC. This study investigated the relationship between CCND1 A870G gene polymorphism and amplification with the development and progression of laryngeal SCC, considering the implications of tumor localization and tobacco exposure. The study population consisted of 66 larynx cancer patients and 110 healthy individuals. CCND1 A/G polymorphism in exon 4 was genotyped by a PCR-RFLP assay. Cyclin D1 gene amplification was evaluated by a Differential-PCR assay and determined by a quantitative densitometric analysis. Our data on gene amplification did not show any correlation with disease stage, histological tumor differentiation, recurrent disease, disease-specific survival or tumor location. However, GG870 genotype was associated with a shorter disease free interval and a reduced overall survival in laryngeal cancer patients. Moreover, this constitutes the first report of a correlation between cyclin D1 A870G polymorphism and increased susceptibility for laryngeal tumor development at the glottic region, which supports the theory of site-specific prevalence of genetic alterations.