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Objective To investigate the effect of the haeme oxygenase-1/carbon monoxide (HO-1/CO) system on atherosclerotic plaque formation and its possible mechanism. Methods For 12 weeks, rabbits were given a 1.5% cholesterol diet (Ch group, n = 8) or a 1.5% cholesterol diet plus an HO-1 inducer, haemin (Hm group, n = 8), or an HO-1 inhibitor, zinc protoporphyrin IX (Znpp-IX, Zn group, n = 8) by intraperitoneal injection. Results Compared with the normal control group (C group, n = 8), serum levels of lipids and oxidised low-density lipoproteins (ox-LDL) increased significantly in all experimental groups (p < 0.01). However, no significant differences were observed among the three experimental groups (p > 0.01). Compared with the control group, aortic nitric oxide (NO) production and nitric oxide synthase (cNOS) activity decreased markedly, whereas carbon monoxide (CO) production and HO-1 activity increased markedly in the Ch group (p < 0.01). This was associated with an increase in the area of aortic plaque of 54.00 ± 4.16%. Compared with the Ch group, CO production and HO-1 activity increased markedly, while aortic HO activity and CO production decreased significantly in the Hm group. The area of aortic plaque was significantly reduced in the Hm group (17.88 ± 3.01%), whereas the area of aortic plaque was significantly increased in the Zn group (61.13 ± 3.50%). Compared with the Ch group, aortic endothlin-1 expression in the Hm group reduced significantly, while in the Zn group it was significantly higher than in the Ch group (p < 0.01). Conclusion The HO-1/CO system plays an inhibitory role in atherosclerotic plaque formation. This role was not mediated by regulating serum lipids and ox-LDL, but was related to the reciprocal relationship between the HO-1/CO and NOS/NO systems in atherosclerosis and the down-regulated expression of endothlin-1 (ET-1), which inhibits the proliferation of vascular smooth muscle cells.