In order to elucidate the controlled-release mechanism of a poorly water-soluble drug from microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend prepared by a phase-separation method, nifedipine-loaded microparticles with different levels of drug loading were evaluated by micromeritic properties, drug physical state, matrix internal structure, drug dissolution, and release modeling. Drug release study indicated that nifedipine release from the microparticles followed the Fickian diffusion mechanism, which supported the study hypothesis that as a result of formation of a nifedipine molecular dispersion, nifedipine dissolution inside the matrix was no longer the rate-limiting step for drug release, and the drug diffusion in matrix became the slowest step instead. Moreover, study results indicated that even though drug loading did not significantly affect the microparticle size distribution and morphology, nifedipine release rate from those microparticles was more or less influenced by the level of drug loading, depending on matrix formulation. At lower levels of drug loading, nifedipine release was well described by the Baker and Lonsdale's matrix diffusion model for microspheres containing dissolved drug and nifedipine had a plasticizing effect on the polymers that caused an increase in drug effective diffusion coefficient with increasing drug loading. However, at higher levels of drug loading, probably due to formation of solid nifedipine domains in microparticles, a change in the release kinetics was observed.