It is now clear the ancestry of all individuals living outside of sub-Saharan Africa is composed of roughly two percent Neandertal ancestry. Yet, it remains largely unclear to what extent this contribution from Neandertals impacts modern human biology, and further, to what extent it may have provided adaptive genetic variation to modern human populations. The immune system is one physiological system that harbors higher than typical amounts of genetic variation in order to provide a flexible set of responses to infection. Here we use coalescent simulation and population genetic approaches to demonstrate a signal of adaptive introgression in the 2'-5' oligoadenylate synthetase (OAS) gene cluster region of chromosome 12. The adaptive region encodes for three active OAS enzymes (OAS1-3) that are involved in the innate immune response to viral infection. In order to evaluate the functional consequences of the adaptive haplotype we infected primary macrophages and peripheral blood mononuclear cells from people with and without the Neandertal haplotype with a panel of bacteria, viruses, and viral-syntetic ligands. Our results show that human cells carrying the Neandertal-like haplotype show marked functional differences in the transcriptional regulation of OAS3 in response to bacterial and viral agents which activate the type I interferon (IFN) production pathway. Additionally, we find that SNPs associated with the Neandertal haplotype are strongly associated with isoform usage in OAS1 and OAS2. These results illuminate the phenotypic effects of Neandertal haplotypes into the regulation of innate immune responses and a potential functional explanation for adaptive introgression of the OAS locus into modern human populations.