Inflammatory mechanisms are proposed to play a significant role in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have described PAH in fat-fed apolipoprotein E knockout (ApoE^−/−) mice. We have reported that signaling in interleukin-1–receptor–knockout (IL-1R1^−/−) mice leads to a reduction in diet-induced systemic atherosclerosis. We subsequently hypothesized that double-null (ApoE^−/−/IL-1R1^−/−) mice would show a reduced PAH phenotype compared with that of ApoE^−/− mice. Male IL-1R1^−/−, ApoE^−/−, and ApoE^−/−/IL-1R1^−/− mice were fed regular chow or a high-fat diet (Paigen diet) for 8 weeks before phenotyping for PAH. No abnormal phenotype was observed in the IL-1R1^−/− mice. Fat-fed ApoE^−/− mice developed significantly increased right ventricular systolic pressure and substantial pulmonary vascular remodeling. Surprisingly, ApoE^−/−/IL-1R1^−/− mice showed an even more severe PAH phenotype. Further molecular investigation revealed the expression of a putative, alternatively primed IL-1R1 transcript expressed within the lungs but not aorta of ApoE^−/−/IL-1R1^−/− mice. Treatment of ApoE^−/− and ApoE^−/−/IL-1R1^−/− mice with IL-1–receptor antagonist prevented progression of the PAH phenotype in both strains. Blocking IL-1 signaling may have beneficial effects in treating PAH, and alternative IL-1–receptor signaling in the lung may be important in driving PAH pathogenesis.