Pre-exposure to volatile anesthetics inhibits inflammation induced by various stimuli, including surgical procedures and ischemia. The authors hypothesized that volatile anesthetics may induce anti-inflammatory effects via a mechanism involving regulation of histone deacetylases (HDACs). Pre-exposure of 1.5% isoflurane for 0.5 h induced anti-inflammatory effects (measured by cytokine production of TNF-ɑ, IL-8, and IL-1β) in both human THP-1 cells and primary human peripheral blood monocytes stimulated by lipopolysaccharide. In human THP-1 cells, co-administration of the HDAC inhibitor trichostatin A blocked the isoflurane-induced anti-inflammatory effects. Trichostatin A also blocked isoflurane-upregulated HDAC1-3 expression and isoflurane-reduced nuclear translocation of p65 and p50 subunits of NF-κB. The ability of isoflurane to reduce NF-κB nuclear translocation and pro-inflammatory responses in the cell line were blocked by gene-silencing of HDAC1 and HDAC2, but not by gene-silencing of HDAC3. A co-immunoprecipitation (co-IP) assay demonstrated that the decreased interaction between HDAC1 and HDAC2 through lipopolysaccharide was restored by isoflurane pre-treatment. These findings were validated in primary human peripheral blood monocytes wherein gene-silencing of HDAC1 and HDAC2 resulted in increased cytokine production and NF-κB nuclear translocation induced by isoflurane pre-exposure and LPS stimulation. These results indicate that anti-inflammatory effects of the volatile anesthetic isoflurane in human monocytes involve regulation of HDAC1 and HDAC2.