The small subpopulation of striatal neurons containing nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d, recently identified as nitric oxide synthase, NOS) is selectively spared in Huntington's disease. Previous search for pathogenic mechanisms capable of destroying striatal neurons but sparing NADPH-d(+) cells has identified only NMDA receptor-mediated excitotoxicity. In view of suggestions that neuronal death in Huntington's disease may occur by apoptosis, we examined the vulnerability of NADPH-d(+) neurons to apoptosis. Murine striatal or cortical cultures exposed to serum deprivation developed extensive neuronal apoptosis, but NADPH-d(+) neurons were relatively spared. This sparing was seen when cultures were exposed to several other apoptosis-inducing insults. It was not seen after toxic exposure to H2O2, and it was not blocked by NOS inhibition. The selective resistance of NADPH-d(+) neurons to several forms of apoptosis provides key support for the possibility that apoptosis may contribute to the pathogenesis of Huntington's disease.