No data exist on the acute effects of statin therapy on human coronary atherosclerotic plaques. The objective of our study was to evaluate the early (<2 months) effects of newly initiated statin therapy on coronary atherosclerosis as evaluated by intravascular ultrasonography. The study population consisted of 74 patients (mean age 58 ± 8 years) who had been included in the ERASE trial (evaluating the effects of reconstituted high-density lipoprotein infusions). All patients underwent serial intravascular ultrasonographic (IVUS) evaluation at baseline (3 ± 2 days after an acute coronary syndrome ACS) and after 6 ± 1 weeks of follow-up. Statin therapy was initiated after ACS in 36 patients who received ≤1 dose of statins before baseline IVUS examination (newly initiated statin therapy group), and 38 patients were already on a stable statin dose before the ACS (long-term statin therapy group). Atorvastatin at a dose of 40 mg/day was the most common regimen in the 2 groups. Percent changes in atheroma volume (prespecified primary efficacy parameter) were −4.71 ± 0.96% in the newly initiated statin therapy group (p <0.0001) and −0.54 ± 0.89% in the long-term statin therapy group (p = 0.546; p = 0.002 for comparison between groups). Median nominal changes in atheroma volume were −9.10 mm3 (interquartile range −12.56 to −3.73, p <0.0001 vs baseline) and 1.21 mm3 (interquartile range −6.41 to 3.76, p = 0.429 vs baseline) in the newly initiated and long-term statin therapy groups, respectively (p = 0.003 for comparison between groups). Greater decreases in total cholesterol (r = 0.25, p = 0.035), ratio of total to high-density lipoprotein cholesterol (r = 0.28, p = 0.018), and high-sensitivity C-reactive protein (r = 0.31, p = 0.046, for patients with high-sensitivity C-reactive protein measurements within 7 days after IVUS examination) were associated with larger percent changes in atheroma volume. In conclusion, newly initiated statin therapy is associated with rapid regression of coronary atherosclerosis within 2 months. This effect was in part associated with decreases in atherogenic lipid and inflammatory parameters. These results provide insight into the rapid clinical benefits of statin therapy after an ACS.