The incorporation of additives such as polyoxyethylated oleic acid glycerides (PEG-derivative) can modify the release of drugs from microparticles. PEG-derivative decreases the release rate of drugs that are dissolved in PLGA matrices but if un-dissolved the initial release rate slightly increases. To clarify this behaviour the influence of adding PEG-derivative in the preparation of microspheres was investigated by scanning electron microscopy, differential scanning calorimetry, gel permeation chromatography, nuclear magnetic resonance and infrared spectroscopy. Cytotoxicity of this resulting PLGA/PEG-derivative matrix was evaluated in cell lines (fibroblasts) which are more reproducible but less specific and in primary cell cultures (splenocytes and human leucocytes) which have the advantage of their specificity. Scanning electron microscopy revealed that PLGA/PEG-derivative microspheres exhibited small surface concavities with a highly porous polymeric matrix. The incorporation of PEG-derivative caused a slight reduction in the T(g) values of PLGA. In vitro degradation studies showed that PEG-derivative remains within the microspheres as long as the matrix does. This PLGA/PEG-derivative matrix was well tolerated exhibiting cell viabilities similar to PLGA microspheres and can be used to modulate the release of drugs from microparticulate systems destined for parenteral administration.