AbstractAdvanced head and neck squamous cell cancer (HNSCC) is currently treated with taxane‐based chemotherapy. We have previously shown that docetaxel (DTX) induces a ras‐dependent survival signal that can be antagonized by farnesyl transferase inhibitors (FTI) such as tipifarnib (TIP). Here we show that the synergistic TIP/DTX combination determines synergistic apoptotic conditions but, at the same time, it modulates the expression of the components of the multichaperone complex that is, in turn, involved in the regulation of the stability of members of the ras‐mediated pathway. Therefore, we have stably transfected HNSCC KB and Hep‐2 cells with a plasmid encoding for HSP90. The expression of the protein was increased in both transfected cell lines but its activation status was increased in Hep‐2 clones and decreased in KB clones. On the basis of these results, we have treated both parental and HSP90‐transfected cells with a HSP90 inhibitor geldanamycin (GA). We have found that the antiproliferative activity of GA is dependent upon the activation status of HSP90 and that it is strongly synergistic when added in combination with TIP but not with DTX in cells overexpressing HSP90 and even more in cells with increased HSP90 activity. These data were paralleled by the decreased expression and activity of the components belonging to the ras→mediated signal transduction pathway. The present results suggest that multichaperone complex activation could be a resistance mechanism to the anti‐proliferative and apoptotic effects induced by TIP and that the combination of FTIs such as TIP with GA could be a suitable therapeutic strategy in the treatment of HSP90‐overexpressing HNSCC. J. Cell. Physiol. 228: 130–141, 2013. © 2012 Wiley Periodicals, Inc.