Tissue transglutaminase (tTG) is a multifunctional enzyme that contributes to disease progression in mouse models of Huntington's disease (HD), an inherited neurodegenerative disease that shows an age-related onset. Moreover, administration of the transglutaminase inhibitor cystamine delays the onset of pathology in the R6/2 HD mouse model. However, the contribution of tTG inhibition towards the therapeutic effects of cystamine has not been determined, as this compound likely has multiple mechanisms of action in the R6/2 mouse. In this study, we found that administration of cystamine in drinking water delayed the age of onset for motor dysfunction and extended lifespan to a similar extent in R6/2 mice that had a normal genetic complement of tTG compared with R6/2 mice that did not express tTG. Since the magnitude of cystamine's therapeutic effects was not affected by the genetic deletion of tTG, these results suggest that the mechanism of action for cystamine in this HD mouse model involves targets other than tTG inhibition.