Head and neck squamous cell carcinomas (HNSCCs) exhibit an increased expression of the translation initiation factor eIF4E and the cell-cycle regulator cyclin D1 (CCND1). Both stimulate cell cycle progression and transform squamous epithelial cells. We used small interfering RNAs (siRNAs) to silence the expression of eIF4E and CCND1 in HNSCC UMSCC22B cells and analyzed the effects of reduced levels of these proteins on colony formation. Transfection of either eIF4E or CCND1 siRNAs decreased the levels of their targeted proteins and inhibited cell growth. siRNA-mediated decrease of eIF4E has led to decreases in the expression of CCND1, basic fibroblast growth factor and vascular endothelial growth factor. Combination of these siRNAs and cisplatin showed more than additive inhibition of colony formation. These findings demonstrate that siRNA silencing of either eIF4E or CCND1 leads to inhibition of the growth of HNSCC cells and suggest that these siRNAs alone or combined with conventional cytotoxic agents may be useful for therapy of HNSCCs.