The relative rates of deamidation, acylation and proteolysis (i.e. amide bond cleavage) were determined for a model peptide (VYPNGA) in poly (DL-lactide-co-glycolide) films. Films were stored at 70°C and either 95%, 75%, 60%, 45%, 28%, or ˜0% relative humidity and at 37°C and 95% relative humidity. Peptide degradation products were identified by ESI+MS/MS and quantitated by LC/MS/MS. Extensive overlap of degradation mechanisms occurred, producing a complex mixture of products. Acylation was the dominant peptide degradation reaction (10–20% of total peptide) at early stages of PLGA hydrolysis and at intermediate relative humidity (60–45% RH). Deamidation and proteolysis were dominant (25–50% and 20–40% of total peptide, respectively) at later stages and at high relative humidity (95–75% RH). Understanding the relative rates of each peptide degradation reaction will allow for improved design of PLGA formulations that preserve the stability of peptide and protein drugs.