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Acylation of peptides is a well-known but unwanted phenomenon in polyester matrices such as poly( d , l -lactic- co -glycolic acid) (PLGA) microspheres used as controlled release formulations. Acylation normally occurs on lysine residues and the N-terminus of the peptide. The purpose of the present work was to assess other possible acylation sites on peptides. Goserelin was used as a model peptide that lacks lysine and a free N-terminus, but contains other nucleophilic residues, i.e. serine, tyrosine and arginine, which potentially can be acylated. Goserelin loaded PLGA microspheres were prepared by a double emulsion solvent evaporation technique. Liquid chromatography ion-trap mass spectrometry (LC-ITMS) was used for determining and monitoring acylation of released goserelin. It is demonstrated that arginine is subjected to acylation with glycolic acid and lactic acid units of PLGA, which was followed by loss of NH 3 from the guanidine group to obtain 2-oxazolin-4-one and 5-methyl-2-oxazolin-4-one residues with masses that are 41 and 55 Da higher, respectively, than the native goserelin. There was no evidence for acylation of serine and tyrosine in goserelin. Our results demonstrate that beside lysine also acylation of arginine can occur in peptides and proteins that are loaded and released from PLGA matrixes. [ABSTRACT FROM AUTHOR]