The aim of this study was to investigate the effect of dietary supplementation with an oil extracted from the zooplankton copepod Calanus finmarchicus [calanus oil (CO)] on atherosclerosis in apoE-deficient (apoE(-/-)) mice. Thirty 6-wk-old female apoE(-/-) mice (n = 10/group) were fed: 1) a Western-type, high-fat diet (HFD); 2) HFD supplemented with 1% (wt:wt) CO; or 3) HFD supplemented with 0.88% (wt:wt) corn oil + 0.12% (wt:wt) EPA+DHA ethyl esters (EPA+DHA) for 13 wk. Dietary CO supplementation lowered total aorta atherogenesis by 36.5% compared to the HFD (P < 0.01), whereas the reduction in the lesion prone aortic arch was 34.8% (P < 0.01). The degree of aortic atherogenesis was intermediate in mice fed EPA+DHA compared to those fed HFD and CO. The effect on atherogenesis was paralleled by reduced expression of hepatic genes for the proinflammatory cytokines, Ccl2, Icam1, Il1b, and Nfkb1, in mice fed CO compared to those fed HFD. For mice fed EPA+DHA, gene expression did not differ compared to those fed CO or HFD. Plasma concentrations of total cholesterol, TG, and cytokines did not differ between the groups at the end of the study. However, mice fed CO gained more weight compared to those fed HFD but not compared to those fed EPA+DHA. In conclusion, dietary CO supplementation attenuated atherosclerotic lesion formation in female apoE(-/-) mice and may be an effective and safe dietary intervention to reduce the development of atherosclerosis. However, further studies are warranted to elucidate the underlying physiological and molecular mechanisms.