Designing materials that regulate cell function in a desired manner is a major goal of biomaterials engineering. Challenges include the vast material property space to be explored, the complexity of cell-surface interactions, and the empirical nature of research in this field. To address these challenges, combinatorial methods have been developed in recent years for screening cell responses to material surfaces. Previous work using gradient libraries of biodegradable polymers poly(epsilon-caprolactone) and poly(D,L-lactide) showed qualitatively that alkaline phosphatase activity of MC3T3-E1 osteoblasts was dramatically enhanced at specific blend compositions and temperatures. In this study, we expand the combinatorial screening to measure quantitatively early events in the osteoblast life cycle: attachment, spreading, and proliferation. In addition, this work relates these cell assays to quantitative measures of polymer surface microstructure and topography. In general, cell attachment was favored on the more hydrophilic PDLA domains. However, cell spreading was strongly influenced by phase-separated microstructures on the polymer surfaces. Regions of enhanced cell proliferation shifted from one microstructural region to others as the culture progressed from 3 to 8 days. Viability showed no response to the surface features of the libraries. These screening results indicate the precise preparatory conditions and microstructure/topography ranges that should be used to design future confirmatory studies of the fundamental mechanisms of cell response to these heterogeneous patterned surfaces. Given the complex nature and breadth of these parameters, the simplification of the parameter space to be explored is an important advance.