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Background Preclinical research indicates that BN82451B has potential to interfere with excitotoxicity, and possesses antioxidant, anti-inflammatory, and mitochondrial protection properties. In-vivo studies in tgHD mice suggested neuroprotective and antidyskinetic effects. Aims The safety and tolerability of BN82451B was tested in Huntington’s Disease (HD) alongside exploratory efficacy with a focus on motor symptoms. Methods This 4-week, randomized, placebo-controlled, double-blind, in-patient, proof-of-concept study explored escalating doses (40 – 80 mg BID) of BN82451B in symptomatic HD subjects. Primary objective was safety and tolerability, secondary objectives were motor symptoms assessed by Q-Motor and the UHDRS-TMS. Results A total of 30 subjects were planned to be included, but the study was terminated after inclusion of 17 subjects (14 BN82451B/3 placebo). Recruitment in this study was complicated by an obligatory in-patient setting at a phase-1 research-unit for four weeks. There were no severe safety issues, but 6 of the 14 treated subjects (43%) developed cutaneous adverse events (rash) which led to discontinuation of treatment in 3 cases and resolved after discontinuation of treatment in all 6 cases. Another 2 subjects were withdrawn due to nausea and vomiting. BN82451B treatment did not differentiate from placebo in the exploratory outcome variables. While placebo subjects showed a mean improvement in the UHDRS-TMS, Q-Motor measures indicated no change in the placebo group. However, mean Q-Motor changes of BN82451B treated patients suggested a none-significant deterioration of motor performance while on drug, which reverted after drug discontinuation. Conclusions BN82451B induced skin rash in 43% of exposed patients and increased nausea/vomiting. Exploratory analysis did suggest a potential for deterioration of motor symptoms in HD subjects under treatment. Q-Motor measures showed much less variance and no placebo response in repeated assessments compared to the UHDRS-TMS. It was decided to discontinue the study.