Background: Solid evidence suggests that atheroscleosis is associated with immune reactions. Most of the activated T cells in the plaque are T helper 1 subtype (Th1), which secrete interferon-gamma (IFN-gamma), now generally accepted as a proatherogenic cytokine. Interferon-alpha (IFN-alpha) has been found to inhibit the secretion of IL-12 and IFN-gamma and to increase IL-10 production. It may, therefore, be atheroprotective. The aim of the present study was to clarify the effect of IFN-alpha on atherogenesis in a transgenic mouse model of atherosclerosis. Methods: 8-week-old low-density lipoprotein (LDL) receptor-deficient mice were allocated randomly into treatment and control groups (n=13 each). The treatment group received 1000 units of IFN-alpha i.p. every other day for 5 weeks and the control mice received 0.9% NaCl. The mice were fed a Western diet. Results: The IFN-alpha-treated and the control mice showed a similar weight gain (mean 3.9+/-1.0 g vs. 3.4+/-1.8 g, respectively). Treatment with IFN-alpha significantly increased the plasma cholesterol levels in both treated and untreated mice (mean 31.03+/-5.53 mmol/l vs. 24.91+/-6.03 mmol/l, respectively; p<0.022) as well as the plasma triglyceride levels (mean 4.79+/-1.57 mmol/l vs. 3.10+/-1.85 mmol/l, respectively; p<0.033). The IFN-alpha treated mice had a significantly increased atherosclerotic plaque area (mean 61,590+/-22,368 microm(2) vs. 37,272+/-15,469 microm(2), respectively; p<0.008). Conclusion: The putative atheroprotective effect of IFN-alpha by the decrease in IL-10 and IFN-gamma is abolished by hyperlipidemia. Therefore, the net effect of IFN-alpha in this murine model is the exacerbation of atherosclerosis.