Microparticles of poly(L-lactic acid) (PLLA), loaded with the antibiotic amoxicillin, have been produced with the SEDS (solution enhanced dispersion by supercritical fluid) process. Encapsulation of amoxicillin in PLLA was initially attempted from a suspension of amoxicillin microparticles in a solution of PLLA in dichloromethane (DCM). In addition, several mixtures of dichloromethane and dimethyl sulfoxide (DMSO), in which amoxicillin and PLLA were dissolved, were employed in an attempt to encapsulate the drug in the biodegradable matrix. The effect of process parameters such as pressure, temperature, concentration of solutes, and DCM/DMSO ratio on the encapsulation efficiency was investigated. In our study, high pressures and a coaxial nozzle for the introduction of the organic solution and the supercritical antisolvent were employed, resulting in the increased mixing of the two flows. An attempt was made to explain the different encapsulation percentages obtained at different operating conditions.