Huntington's disease results from a mutation in the HD gene encoding for the protein huntingtin. The function of huntingtin, although beginning to be elucidated, remains largely unclear. To probe the prosurvival function of huntingtin, we modulate levels of wild‐type huntingtin in a number of cellular and in vivo models. Huntingtin depletion resulted in caspase‐3 activation, and overexpression of huntingtin resulted in caspase‐3 inhibition. Additionally, we demonstrate that huntingtin physically interacts with active caspase‐3. Interestingly, mutant huntingtin binds active caspase‐3 with a lower affinity and lower inhibitory effect on active caspase‐3 than does wild‐type huntingtin. Although reduction of huntingtin levels resulted in caspase‐3 activation in all conditions examined, the cellular response was cell‐type specific. Depletion of huntingtin resulted in either overt cell death, or in increased vulnerability to cell death. These data demonstrate that huntingtin inhibits caspase‐3 activity, suggesting a mechanism whereby caspase‐mediated huntingtin depletion results in a detrimental amplification cascade leading to further caspase‐3 activation, resulting in cell dysfunction and cell death.