Interleukin-4 (IL-4) has been detected in both human and mouse atherosclerotic lesions, although its effects on the development of the disease are undefined. We determined the role of IL-4 in the most commonly used murine models of atherosclerosis by defining the effects of exogenous delivery and genetic deficiency of this cytokine on both hypercholesterolemia and AngII-induced atherosclerosis in apolipoprotein E (apoE)^−/− mice and different dietary stimuli in low-density lipoprotein (LDL) receptor^−/− mice. Exogenous administration of IL-4 (1.1 ng g⁻¹ day⁻¹ i.p. for 30 days) into female apoE^−/− mice had no effect on lesion size or composition in mice fed normal or saturated fat diets. Also, IL-4 deficiency had no significant effect on the size or composition of atherosclerotic lesions in two vascular areas of male and female apoE^−/− mice fed either a normal or saturated fat diet. IL-4 deficiency was also studied in age-matched male mice infused with AngII (1000 ng kg⁻¹ min⁻¹) for 28 days. Whereas AngII infusion augmented atherosclerotic lesion formation, IL-4 deficiency did not influence atherosclerotic lesion size or composition. Finally, different dietary stimuli also had no effect on atherosclerotic lesion size in female LDL receptor^−/− mice. These data demonstrate that IL-4 does not significantly influence the development of atherosclerotic lesions in apoE^−/− mice of either gender or in female LDL receptor^−/− mice, irrespective of the mode of induction of atherosclerosis.