Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a glutamine expansion in the Huntingtin protein. HD is characterised by loss of muscle coordination and cognitive impairment resulting in death 15-20 years after onset of symptoms. Presently, with no cure, only palliative care is available to patients. The diverse functions attributed to the Huntingtin protein and the lack of effective animal models continues to hamper therapeutic development. We propose that HD-affected human embryonic stem cells (hESC) differentiated to neural cell types replicate molecular mechanisms involved in disease pathology and progression. The immortality of hESC combined with robust differentiation protocols provides a high-throughput, relevant, genetically unmodified model for drug development which reduces costs associated with tissue biopsies and animal models. HD-affected stem cell lines were derived from embryos found by pre-implantation genetic diagnosis to carry the HD mutation and therefore donated by consenting couples for research. HD-affected and unaffected hESC were differentiated into mature neural phenotypes and a comparative shotgun proteomic analysis performed. We identified 136 proteins that were significantly differentially expressed in HD-affected neural cells. Primarily, we observed six members of the histone H1 family, not previously identified as a major contributor to gene expression perturbations in HD, to be significantly up-regulated in HD-affected cells. Also, 34 cytoskeletal proteins including 10 involved in axonal development and neurite extension were found to be down-regulated. Analysis of the protein data using Ingenuity Pathway Analysis software suggested that differentially expressed proteins are involved in actin cytoskeleton maintenance, EIF2 and ILK signalling. EIF2 signalling is essential for initiation of translation and ILK signalling regulates multiple cellular functions including cell migration, proliferation, adhesion and signal transduction. This examination of whole proteomes of neurodifferentiated hESC offers insight to HD pathology while generating a comprehensive list of potential biomarkers.