Relative changes in lumen size during progression and regression of coronary atherosclerosis remain largely unknown. We assessed these changes using serial intravascular ultrasound (IVUS). From the baseline IVUS interrogations of the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, 210 focal coronary lesions with <50% angiographic stenosis were identified. Lesions were matched to the follow-up IVUS, performed after 18 months of treatment with atorvastatin 80 mg/day or pravastatin 40 mg/day. Changes in external elastic membrane (EEM) and lumen areas of lesions demonstrating progression and regression (i.e. increased and decreased atheroma area) were examined. In progressors (n=128), there was 1.34 mm(2) increase in EEM area for every 1mm(2) increase in atheroma area (r=0.72, p<0.0001). This resulted in 0.34 mm(2) increase in lumen area for every 1mm(2) increase in atheroma area (r=0.25, p=0.004). In contrast, there was no significant change in lumen area with regression of disease (n=82, r=-0.06, p=0.59). Progression of coronary atherosclerosis can be associated with a paradoxical increase in lumen cross-sectional area, whereas regression is not associated with any change in lumen area. Measurement of changes in lumen size may not be an accurate method to study progression and regression of atherosclerotic lesions with <50% stenosis.