Controlling cellular and physiological responses such as adhesion, proliferation and migration is a highly desirable feature of engineered scaffolds. One important application would be the design of tissue engineered vascular grafts that regulate cell adhesion and growth. We utilized temperature-composition combinatorial polymer libraries to investigate the effects of surfaces of blended poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(epsilon-caprolactone) (PCL) on murine vascular smooth muscle cells (SMC). In this manner, SMCs were exposed to approximately 1000 distinguishable surfaces in a single experiment, allowing the discovery of optimal polymer compositions and processing conditions. SMC adhesion, aggregation, proliferation, and protein production were highest in regions with mid- to high-PCL concentrations and high annealing temperatures. These regions exhibited increased surface roughness, increased microscale PLGA-rich matrix stiffness, and significant change of bulk PCL-rich crystallinity relative to other library regions. This study revealed a previously unknown processing temperature and blending composition for two well-known polymers that optimized SMC interactions.