Background: Multiple system atrophy (MSA) is a rare oligodendroglial synucleinopathy of unknown etiopathogenesis including two major clinical variants with predominant parkinsonism (MSA-P) or cerebellar dysfunction (MSA-C). Objective: To identify novel disease mechanisms we performed a blood transcriptomic study investigating differential gene expression changes and biological process alterations in MSA and its clinical subtypes. Methods: We compared the transcriptome from rigorously gender and age-balanced groups of 10 probable MSA-P, 10 probable MSA-C cases, 10 controls from the Catalan MSA Registry (CMSAR), and 10 Parkinson Disease (PD) patients. Results: Gene set enrichment analyses showed prominent positive enrichment in processes related to immunity and inflammation in all groups, and a negative enrichment in cell differentiation and development of the nervous system in both MSA-P and PD, in contrast to protein translation and processing in MSA-C. Gene set enrichment analysis using expression patterns in different brain regions as a reference also showed distinct results between the different synucleinopathies. Conclusions: In line with the two major phenotypes described in the clinic, our data suggest that gene expression and biological processes might be differentially affected in MSA-P and MSA-C. Future studies using larger sample sizes are warranted to confirm these results. Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterized by autonomic failure and an early motor predominance of cerebellar symptoms such as ataxia (MSA-C) or a poor levodopa responsive parkinsonism (MSA-P) 1. Pathologically, MSA can encompass predominant olivopontocerebellar atrophy or striatonigral degeneration with neuronal loss, gliosis and glial cytoplasmatic inclusions (GCI) mainly containing aggregated α-synuclein (SNCA), among other proteins. The two pathological distributions correlate with the clinical phenotype, although in late stages most cases have mixed clinicopathological profiles 2. Clinical consensus guidelines are key for diagnosis allowing for an up to probable diagnosis; however definite diagnosis requires neuropathological confirmation 3. Although following consensus criteria improves diagnostic accuracy significantly 4,5 , in the clinic about 20 6 to 40% 7 of patients are still misdiagnosed. Etiologically, MSA is a rare and sporadic disease with few recognized monogenic causes 8. Association of genetic risk polymorphisms in the SNCA 9 and the MAPT 10 genes among others have been reported 11-13 , but results have not always been replicated. SNCA mRNA or protein expression level studies in specific brain regions have also been controversial 14-16. More recently, transcriptional pathways regulating gene expression have been explored in MSA brains 17,18 , identifying differentially expressed candidate genes potentially involved in the pathological cascade of MSA 19. A limitation to most studies is linked to the clinical heterogeneity of MSA, which