The objective was to assess outcomes of IFNgamma-priming upon macrophage activation by the synovial macromolecule high molecular weight hyaluronan [HMW-HA] in the context of rheumatoid arthritis inflammation. Human macrophages primed by IFNgamma and activated by HMW-HA were evaluated for cytokine secretion by ELISA and Milliplex assay and activation profiles by nuclear transcription factor EIA. IFNgamma-primed, HMW-HA-activated macrophages produced elevated levels of TNF and secreted the TH1 cytokine IL-12p70, while IFNgamma suppressed HMW-HA-induced secretion of the regulatory cytokine IL-10 and activation of the transcription factor c-Jun. IFNgamma modulates the HMW-HA-induced cytokine response profile promoting macrophage activation and inflammatory TH1 cytokine secretion.