The ability to control blood vessel assembly in polymer scaffolds is important for clinical success in tissue engineering. A mathematical and computational representation of the relationship between scaffold properties and neovascularization may provide a better understanding of the fundamental process itself and help guide the design of new therapeutic approaches. This article proposes a multilayered, multiagent framework to model sprouting angiogenesis in porous scaffolds and examines the impact of pore structure on vessel invasion and network structure. We have defined the speed of vessel sprouting in the agent-based model based on in vivo results in the absence of a polymer scaffold. A number of cases were run to investigate the effect of scaffold pore size on angiogenesis. The simulation results indicate that the rate of scaffold vascularization increases with pore size. Pores of larger size (160-270 μm) support rapid and extensive angiogenesis throughout the scaffold. Model predictions were compared to experimental results of vascularization in porous poly(ethylene glycol) hydrogels to validate the results. This model can be used to provide insight into optimal scaffold properties that support vascularization of engineered tissues.