Abstract: Objective To study the effect of lipid smoothness on progression of atherosclerosis in rabbits. Methods Twenty-four male New Zealand rabbits were randomly divided into blank group (group A, n=6), control group (group B, n=9), and lipid fluctuation group (group C, n=9), and fed with normal diet, continuous high fat diet, and high fat diet, respectively, for 12 weeks, followed by low-fat diet every 3 weeks for 24 weeks. Their serum lipid and hs-CRP levels were measured at weeks 0 and 12 when the high fat diet was changed. The abdominal aorta was examined by ultrasonography. Pathologic changes of aorta were observed and their severity was analyzed. Results The serum levels of TC, TG, LDL-C and hs-CRP were significantly higher in groups B and C than in group A at week 12 ((37.36±1.82) mmol/L, (2.30±1.46) mmol/L, (40.33±2.32) mmol/L, (0.40±0.10) mg/dl and (34.96±6.98) mmol/L, (1.48±0.82) mmol/L, (34.65±7.94) mmol/L, (0.45±0.11) mg/dl vs (0.78±0.24) mmol/L, (0.61±0.44) mmol/L, (0.27±0.13) mmol/L, (0.17±0.04) mg/dl, P< 0.01). The lipid smoothness index (SI) of TC and LDL-C was significantly lower in group C than in group B(12.51 and 7.61 vs 3.60 and 3.29, P< 0.05) while the serum levels of TC, TG, LDL-C and hs-CRP were higher in both groups B and C, and the serum hs-CRP level was significantly higher in group C than in group B at week 24 ((0.53±0.07) mg/dl vs (0.45±0.06)mg/dl, P< 0.05). The IMT of abdominal aorta was significantly greater in groups B and C than in group A at week 12 ((0.70±0.11) mm and (0.84±0.14) mm vs (0.40±0.01) mm, P< 0.05) and in group C than in group B at week 24 ((1.10±0.21) mm vs (0.77±0.11) mm, P< 0.05). The incidence of endoaortic atherosclerotic plaques was significantly higher in group C than in group B (53.53%±22.6%vs 33.90%±24.91%, P< 0.05). However, the plaques in fibrous cap were thinner in group C than in group B ((103.50±45.66)μm vs (295.83±97.90) μm, P< 0.01). Discontinuous fibrous cap could be observed under optical microscopy. Conclusion Lipid smoothness is associated with the progression of atherosclerosis. The lower the lipid SI is, the faster the plaques develop, which may be related with the exacerbated inflammation.