Nucleic acids interacting with pattern-recognizing receptors (PRRs), such as Toll-like-(TLRs), RIG-I-like receptors (RLRs) and dsDNA-receptors activate innate immune response in non-professional immune cells and thus the production of pro-inflammatory cytokines. Along with bacterial and viral nucleic acids, endogenous cell-free and cell-surface-bound extracellular DNA (exDNA and csbDNA) could interact with PRRs and possess immunomodulating activity. To elucidate if exDNA influence innate immunity a comparative study of exDNA, genomic and plasmid DNA on interleukin production in gingival fibroblasts (GF) has been done. All DNA tested have no effect on IL secretion in a broad concentration range (10 ng/ml-1 μg/ml). Simultaneous treatment of cells with DNA and dsRNA analog poly(I:C) leads to inhibition of poly(I:C)-activated secretion of IL-6 and IL-8. Cell-surface-bound DNA possesses two times stronger inhibiting effect as compared to genomic DNA indicating the enrichment of csbDNA in sequences providing such activity. Effects of several recently found specific DNA sequences tightly bound with cell surface have been tested. Joint stimulation of GF with poly(I:C) and deoxyribooligonucleotides (ODN), containing such sequences, demonstrates that both ssODN and dsODN possess sequence-dependent inhibiting effect. Inhibition of IL production after colipofection of ODN and poly(I:C) into cells indicates the involvement of RLRs or other cytoplasmic factors in the effect. The data obtained indicate that endogenous DNA might be involved in regulation of antiviral immune response and sequence-specific ODNs are potential inhibitors of the inflammation induced by viral infection.