Huntington’s and Parkinson’s Diseases (HD and PD) are neurodegenerative disorders that share some pathological features but are disparate in others. For example, while both diseases are marked by aberrant protein aggregation in the brain, the specific proteins that aggregate and types of neurons affected differ. A better understanding of the molecular similarities and differences between these two diseases may lead to a more complete mechanistic picture of both the individual diseases and the neurodegenerative process in general. We sought to characterize the common transcriptional signature of HD and PD as well as genes uniquely implicated in each of these diseases using mRNA-Seq data from post mortem human brains in comparison to neuropathologically normal controls. The enriched biological pathways implicated by HD differentially expressed genes show remarkable consistency with those for PD differentially expressed genes and implicate the common biological processes of neuroinflammation, apoptosis, transcriptional dysregulation, and neuron-associated functions. Comparison of the differentially expressed (DE) genes highlights a set of consistently altered genes that span both diseases. In particular, processes involving nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and transcription factor cAMP response element-binding protein (CREB) are the most prominent among the genes common to HDand PD. When the combined HDand PDdata are compared to controls, relatively few additional biological processes emerge as significantly enriched, suggesting that most pathways are independently seen within each disorder. Despite showing comparable numbers of DE genes, DE genes unique to HD are enriched in far more coherent biological processes than the DE genes unique to PD, suggesting that PD may represent a more heterogeneous disorder. The complexity of the biological processes implicated by this analysis provides impetus for the development of better experimental models to validate the results.