By crossing Huntington's disease (HD) R6/1 transgenic mice with ‘tissue’transglutaminase (TG2) knock-out mice, we have demonstrated that this multifunctional enzyme plays an important role in the neuronal death characterising this disorder in vivo. In fact, a large reduction in cell death is observed in R6/1, TG2−/− compared with R6/1 transgenic mice. In addition, we have shown that the formation of neuronal intranuclear inclusions (NII) is potentiated in absence of the ‘tissue’transglutaminase. These phenomena are paralleled by a significant improvement both in motor performances and survival of R6/1, TG2−/− versus R6/1 mice. Taken together these findings suggest an important role for tissue transglutaminase in the regulation of neuronal cell death occurring in Huntington's disease.