Potent statin therapy has been demonstrated to reduce cardiovascular events. Although statins have been considered to stabilize atherosclerotic plaque, this effect has not been well characterized in vivo. We investigated the relation between potent statin therapy and plaque microstructures imaged by frequency-domain optical coherence tomography. Two hundred ninety nonculprit lipid plaques in 275 patients with stable coronary artery disease receiving atorvastatin or rosuvastatin were analyzed. Patients were stratified into no statin, low-, and high-dose statin groups. Plaques in the high-dose statin group demonstrated a smaller lipid arc (p = 0.02) and a greater fibrous cap thickness (p = 0.01). In patients receiving statin therapy, high-dose statin therapy was associated with a greater fibrous cap thickness in patients with smaller (148.2 ± 30.5 vs 105.3 ± 41.1 μm, p = 0.004) but not larger lipid index (91.1 ± 32.6 vs 78.1 ± 43.3 μm, p = 0.21). In conclusion, potent statin therapy is associated with less vulnerable plaque features on frequency-domain optical coherence tomography imaging. This finding varies according to the size of plaque lipid content, being less effective in lipid-loaded plaques.