Background: The focal distribution of atherosclerotic plaques suggests that local biomechanical factors may influence plaque development. Methods and Results: We studied 40 patients at baseline and over 12 months by virtual-histology intravascular ultrasound and bi-plane coronary angiography. We calculated plaque structural stress (PSS), defined as the mean of the maximum principal stress at the peri-luminal region, and wall shear stress (WSS), defined as the parallel frictional force exerted by blood flow on the endothelial surface, in areas undergoing progression or regression. Changes in plaque area (PA), plaque burden (PB), necrotic core (NC), fibrous tissue (FT), fibrofatty tissue (FF) and dense calcium (DC) were calculated for each co-registered frame. A total of 4029 co-registered frames were generated. In areas with progression, high PSS was associated with larger increases in NC and small increases in FT vs. low PSS (difference inΔNC: 0.24±0.06mm2; p<0.0001, difference in ΔFT: -0.15±0.08 mm2; p=0.049). In areas with regression, high PSS was associated with increased NC and decreased FT (difference in ΔNC: 0.15±0.04; p=0.0005, difference in ΔFT: -0.31±0.06mm2; p<0.0001). Low WSS was associated with increased PB vs. high WSS in areas with progression (difference in ΔPB: 3.3±0.4%; p<0.001) with a similar pattern observed in areas with regression (difference in ΔPB: 1.2±0.4%; p=0.004). PSS and WSS were largely independent of each other (R2 =0.002; p=0.001). Conclusions: Areas with high PSS are associated with compositional changes consistent with increased plaque vulnerability. Areas with low WSS are associated with more plaque growth in areas that progress and less plaque loss in areas that regress. The interplay of PSS and WSS may govern important changes in plaque size and composition.