We examined the expression of IL-33 as an indicator of an innate immune response in relapsing remitting MS (RRMS) and controls. Based on our previous studies we proposed a link between the expression of IL-33 and IL-33 regulated genes to histone deacetylase (HDAC) activity and in particular HDAC3, an enzyme that plays a role in the epigenetic regulation of a number of genes including those which regulate inflammation. Our studies showed that intracellular expressions of IL-33 and IL-33 regulated genes are increased in patients with RRMS. In addition, following culture with TLR agonist lipopolysaccharide (LPS), there is increased induction of both IL-33 and HDAC3 in RRMS patients over that seen in controls. Also, culture of PBMC with IL-33 led to the expression of genes which overlapped with that seen in RRMS patients suggesting that the gene expression signature seen in RRMS may be driven by innate immune pathways. Expression of levels of IL-33 but not IL-1β (another gene regulated by TLR agonists) is completely inhibited by Trichostatin A (TSA) establishing a closer regulation of IL-33 but not IL-1β with HDAC. These results demonstrate the over expression of innate immune genes in RRMS and offer a causal link between the epigenetic regulation by HDAC and the induction of IL-33.