Background: A subclinical, hepatic involvement in manifest and premanifest Huntington's disease (HD) was recently demonstrated by using the ¹³C-methionine breath test (MeBT). In this longitudinal pilot study, we investigated whether there is evidence for progressive hepatic mitochondrial dysfunction in premanifest HD. Methods: The MeBT was performed within a group of 25 well-characterized premanifest HD mutation carriers at baseline and in a 14.5-month follow-up. Results: The total group of mutation carriers (P=0.033; Cohen's d=0.6) and the subgroup of mutation carriers from our PreHD-B subgroup (nearer to disease onset; P=0.030; Cohen's d=1.12) revealed a lower amount of exhaled ¹³CO₂ in the follow-up. Conclusions: This study demonstrates in vivo progressive, subclinical, hepatic involvement in premanifest HD. Limitations of the study, such as high variance in breath test results, are discussed.