Atorvastatin and rosuvastatin are both highly effective in decreasing low-density lipoprotein cholesterol and triglyceride levels. However, rosuvastatin was shown to be more effective in increasing high-density lipoprotein (HDL) cholesterol levels. The purpose of the study is to compare the effects of daily doses of rosuvastatin 40 mg with atorvastatin 80 mg during a 6-week period on HDL subpopulations in 306 hyperlipidemic men and women. We previously showed that increased levels of large alpha-1 and alpha-2 HDLs decrease the risk of coronary heart disease and protect against progression of coronary atherosclerosis (superior to HDL cholesterol). In this study, both statins caused significant increases in large alpha-1 (p <0.001) and alpha-2 (p <0.001 for rosuvastatin, p <0.05 for atorvastatin) and significant (p <0.001) decreases in small pre-beta-1 HDL levels; however, increases in the 2 large HDL particles were significantly higher for rosuvastatin than atorvastatin (alpha-1, 24% vs 12%; alpha-2, 13% vs 4%; p <0.001). Statin-induced increases in alpha-1 and alpha-2 correlated with increases in HDL cholesterol, whereas decreases in pre-beta-1 were associated with decreases in triglycerides. In subjects with low HDL cholesterol (<40 mg/dl for men, <50 mg/dl for women, n = 99), increases in alpha-1 were 32% versus 11%, and in alpha-2, 21% versus 5% for rosuvastatin and atorvastatin, respectively. In conclusion, our data show that both statins, given at their maximal doses, favorably alter the HDL subpopulation profile, but also that rosuvastatin is significantly more effective in this regard than atorvastatin.