A proportion of differentiated SH-SY5Y cells undergo cell death in response to withdrawal of serum. This death manifests the hallmark features of apoptosis including changes in nuclear morphology, processing and activation of caspase 3 and cleavage of the caspase 3 substrates acetyl-Asp-Glu-Val-Asp-aminomethylcoumarin and poly(ADP-ribose) polymerase. These findings represent the first demonstration of serum withdrawal induced apoptosis in SH-SY5Y cells. The reduction in viability induced by serum deprivation and assessed using an inhibitor of mitochondrial respiration can be partially inhibited by FK506, but FK506 does not prevent caspase 3 processing or cleavage of caspase 3 substrates. FK506 is also able to promote the viability of a small proportion of embryonic mouse sensory neurons following nerve growth factor-withdrawal induced apoptosis. FK506 did not promote viability in either cell type in the absence of serum- or nerve growth factor-withdrawal. These observations are consistent with a survival-promoting effect of FK506 in cultured neurons.