There is evidence from in vitro and animal experiments that oral creatine (Cr) supplementation might prevent or slow down neurodegeneration in Huntington's disease (HD). However, this neuroprotective effect could not be replicated in clinical trials, possibly owing to treatment periods being too short to impact on clinical endpoints. We used proton magnetic resonance spectroscopy ((1)H-MRS) as a surrogate marker to evaluate the effect of Cr supplementation on brain metabolite levels in HD.Twenty patients (age 46+/-7.3 years, mean duration of symptoms 4.0+/-2.1 years, number of CAG repeats 44.5+/-2.7) were included. The primary endpoint was metabolic alteration as measured by (1)H-MRS in the parieto-occipital cortex before (t1) and after 8-10 weeks (t2) of Cr administration. Secondary measures comprised the motor section of the Unified Huntington's Disease Rating Scale and the Mini Mental State Examination. (1)H-MRS showed a 15.6% decrease of unresolved glutamate (Glu)+glutamine (Gln; Glu+Gln=Glx; p<0.001) and a 7.8% decrease of Glu (p<0.027) after Cr treatment. N-acetylaspartate trended to fall (p=0.073) whereas total Cr, choline-containing compounds, glucose, and lactate remained unchanged. There was no effect on clinical rating scales. This cortical Glx and Glu decrease may be explained by Cr enhancing the energy-dependent conversion of Glu to Gln via the Glu-Gln cycle, a pathway known to be impaired in HD. Since Glu-mediated excitotoxicity is presumably pivotal in HD pathogenesis, these results indicate a therapeutic potential of Cr in HD. Thus, longterm clinical trials are warranted.