IL-6, an inducer of the acute-phase response, is linked with the development of vascular disease and atherosclerosis. One mechanism likely involves direct effects of IL-6 on vascular smooth muscle cells (VSMC), for IL-6 can induce VSMC proliferation and the release of monocyte chemoattractant protein-1 (MCP-1). We hypothesized that this stimulation occurs via the JAK (janus-activated kinase)/STAT (signal and transducers and activators of transcription) signaling pathway. Rat VSMC were stimulated with IL-6 in the presence or absence of a JAK 2 inhibitor, and the activation of STAT 3 (by Western), MCP-1 (by ELISA) and DNA synthesis (by 3 H-thymidine incorporation) was determined. IL-6 rapidly induced phosphorylation of STAT 3 in a dose-and time-dependent manner with a peak expression at 30 min. IL-6 also stimulated MCP-1 protein production and DNA synthesis dose dependently. 50 µM of AG490, a specific JAK 2 inhibitor, partially inhibited STAT 3 activation and MCP-1 production, with near complete inhibition of DNA synthesis. The JAK/STAT pathway partially mediates IL-6-induced MCP-1 production and DNA synthesis in rat VSMC. These studies implicate a role of the JAK/STAT pathway in the development of vascular disease and atherosclerosis.