Mutations in the LMNA gene causes abnormalities in nuclear structure and alterations in gene expression which may lead to increased susceptibility to damage in response to stress, resulting in a variety of diseases termed laminopathies. Lamin A has been shown to interact with a variety of proteins, including heat shock factor (hsf) 2, which induces heat shock protein (hsp) transcription during the stress response. The purpose of this study was to determine if the interaction of lamin A and hsf2 is required for hsf2 activity, the subsequent induction of hsp70, and the activation of a cellular defense pathway. We propose that the decrease in this protective response is one mechanism which may cause LMNA-/- cells to be more susceptible to death. We show that LMNA is required for the nuclear localization of hsf2, as the absence of LMNA causes the translocation of hsf2 from the nucleus to the cytoplasm, where hsf2 is inactive. Additionally, LMNA-/- cells have impaired induction of hsp70 in response to the hsf2 activator, MG132, compared to LMNA+/+ fibroblasts. Subsequently, LMNA -/- fibroblasts are more susceptible to apoptotic death induced by MG132. These results demonstrate that the interaction of lamin A with hsf2 is required to maintain nuclear hsf2 and induce hsp70 expression. The inability of LMNA-/- cells to activate hsf2 and induce hsp70 may be one mechanism which causes LMNA-/- cells to be more susceptible to apoptosis.