Previous work suggests N-methyl-D-aspartate receptor (NMDAR) activation may be involved in degeneration of medium-sized spiny striatal neurons in Huntington's disease (HD). Here we show that these neurons are more vulnerable to NMDAR-mediated death in a YAC transgenic FVB/N mouse model of HD expressing full-length mutant huntingtin, compared with wild-type FVB/N mice. Excitotoxic death of these neurons was increased after intrastriatal injection of quinolinate in vivo, and after NMDA but not AMPA exposure in culture. NMDA-induced cell death was abolished by an NR2B subtype-specific antagonist. In contrast, NMDAR-mediated death of cerebellar granule neurons was not enhanced, consistent with cell-type and NMDAR subtype specificity. Moreover, increased NMDA-evoked current amplitude and caspase-3 activity were observed in transgenic striatal neurons. Our data support a role for NR2B-subtype NMDAR activation as a trigger for selective neuronal degeneration in HD.