Abstract Purpose The removal of the residual solvent dichloromethane from biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles was investigated by aqueous or alcoholic wet extraction or vacuum-drying. Methods Microparticles were prepared by the O/W solvent extraction/evaporation method. The solidified microparticles were separated by filtration and the effect of subsequent drying and wet extraction methods were investigated. The residual solvent content was analysed with gas chromatography (organic solvents) and Karl Fischer titration (water). The effect of extraction conditions on microparticle aggregation, surface morphology and encapsulation of the drugs dexamethasone and risperidone was investigated. Results Residual dichloromethane was reduced to 2.43% (w/w) (20 °C) or 0.03% (w/w) (35 °C) by aqueous wet extraction. With vacuum-drying, residual dichloromethane only decreased from about 5% (w/w) to 4.34% (w/w) (20 °C) or 3.20% (w/w) (35 °C) due to the lack of the plasticizing effect of water. Redispersion of filtered, wet microparticles in alcoholic media significantly improved the extraction due to an increased PLGA plasticization. The potential of different extractants was explained with the Gordon-Taylor equation and Hansen solubility parameters. Extraction in methanol: or ethanol:water mixtures reduced residual dichloromethane from 4 - 7% (w/w) to 0.5 - 2.3% (w/w) within 1 h and 0.08 - 0.18% (w/w) within 6 h. Higher alcohol contents and higher temperature resulted in aggregation of microparticles and lower drug loadings. Conclusion The final removal of residual dichloromethane was more efficient with alcoholic wet extraction followed by aqueous wet extraction at elevated temperature and vacuum drying of the microparticles.