Spray-drying, the (w/o)w solvent evaporation method and the aerosol solvent extraction system (ASES) were used to study the influence of the preparation method on residual solvents in microspheres. Poly(L-lactic acid) and poly(DL-lactic-co-glycolic acid) (75:25) were selected as polymers and methanol, methylene chloride and chloroform were used as solvents to prepare drug-free and tetracosactide (model peptide) loaded microspheres. The residual solvent contents of the microparticles were determined by multiple headspace extraction from the solid samples. In all batches, residual methanol was well below the limit of 1000 ppm (Rabiant, 1991), whereas residual methylene chloride was only well below the USP XXIII limit of 500 ppm in batches prepared by spray drying at an inlet temperature of 60°C. The lowering of the inlet temperature to 50°C led to increased residual methylene chloride concentrations ranging from 300 to 700 ppm. In case of ASES even higher residual methylene chloride contents were obtained. However, when dried under mild conditions (3 days, room temperature, 35 kPa) all batches satisfied the requirements, with the exception of batches containing chloroform (prepared by spray drying at an inlet temperature of 60°C), which could not be efficiently removed. Additionally, morphology, particle size distribution, drug loading and encapsulation efficiencies of the batches prepared by the different methods were studied comparatively.