An oil-in-water (O/W) solvent evaporation method was used to prepare biodegradable rnicrospheres based on poly(D,L-lactic acid) (PLA). Nifedipine, a hydrophobic drug, was chosen as a model molecule in the study of drug entrapment and release. Effect of preparation conditions on the size, morphology, drug loading, and release profiles of micropheres was investigated. Based on in vitro release experimental findings, a diffusion/dissolution model was presented for quantitative description of the resulting release behaviors and drug release kinetics from PLA microspheres analyzed. The mathematical models were used to predict the effect of nucrostructure on the resulting drug release. It provided an approach to determine the suitable structure parameters for microspheres to achieve desired drug release behaviors.