The extracellular matrix proteoglycan versican is often present in the neoplastic microenvironment and has been shown to mediate apoptotic resistance in a number of different model systems. As presented here, V1 versican-transfected fibroblasts downregulated the pro-apoptotic protein Fas. While resistance to apoptosis is a hallmark of cancers, tumours are also almost uniformly sensitized to specific apoptotic insults. It was hypothesized that V1-transfected cells would also show evidence of pro-apoptotic signaling. Consistent with this, increased p53 protein levels were found. These cells showed strong sensitization to UV, chemotherapeutics and hypoxia mimetics, each which signals through p53. This study provides evidence of concomitant resistance and sensitivity to different apoptotic stimuli following versican overexpression. Observed anti-apoptotic changes may be physiologic compensations for pro-apoptotic events caused by versican, perhaps in response to increased proliferation. These results mimic what occurs in cancer progression and suggest a relevant role for versican in this phenomenon.