Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder linked to a mutation in the huntingtin gene leading to protein aggregation in neurons. The generation of new neurons in neurogenic regions, such as the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus, is affected by these aggregation processes. In particular, hippocampal neurogenesis is reduced in the R6/2 transgenic mouse model of HD. Since physical activity stimulates adult hippocampal neurogenesis, we examined whether running is capable to rescue the impaired hippocampal neurogenesis in R6/2 mice. Proliferation of hippocampal cells measured by proliferating cell nuclear antigen (PCNA) marker was reduced in R6/2 animals by 64% compared to wild type mice. Accordingly, newly generated neurons labeled with doublecortin (DCX) were diminished by 60% in the hippocampus of R6/2 mice. Furthermore, the number of newly generated mature neurons was decreased by 76%. Within the hippocampus of wild type animals, a four-week running period resulted in a doubling of PCNA-, DCX-, and bromo-deoxyuridine (BrdU)-labeled cells. However, physical exercise failed to stimulate proliferation and survival of newly generated neurons in R6/2 transgenic mouse model of HD. These findings suggest that mutant huntingtin alters the hippocampal microenvironment thus resulting in an impaired neurogenesis. Importantly, this adverse microenvironment impeded neurogenesis upregulation such as induced by physical exercise. Future studies need to decipher the molecular pathways involved in repressing the generation of new neurons after physical activity in huntingtin transgenic rodents.