Abstract The effects of temperature and concentration on leuprolide degradation in dimethyl sulfoxide (DMSO) were explored. Leuprolide degradation products were analyzed by reverse phase high-performance liquid chromatography (RP–HPLC), size exclusion chromatography (SEC) and structurally characterized by mass spectrometry. Leuprolide solution stability in DMSO was characterized at 50, 100, 200, 400 mg/ml at 37–80°C for 2 months to 3 years. Leuprolide degradation products were identified by mass spectrometry and could generally be attributed to isomerization, hydrolysis, oxidation, or aggregation. The hydrolytic degradation products consisted primarily of backbone cleavage C-terminal to Trp 3, Ser 4, Tyr 5, Leu 6 and Leu 7, and oxidation of Trp 3 and β-elimination of Ser 4 were identified. Leuprolide degradation at 50°C, 65°C and 80°C proceeded in an exponential fashion ( E a=22.6±1.2 kcal/mol); however, leuprolide degradation plateau’d after approximately 6 months at 37°C. Upon closer examination, degradation product peak areas were seen to vary with temperature. For example, aggregation products did not increase with time at 37°C, but aggregation peak intensities increased sharply with time at 80°C. Increasing the temperature also increased the proportion of leuprolide degrading via isomerization/hydrolytic pathways, and decreased the proportion degrading via oxidation. These variations suggested that solvent dielectric, free H + in an aprotic solvent, oxygen solubility, impurities and residual moisture may play a role. Leuprolide solubilized in DMSO yields adequate stabililty for a 1 year implantable osmotic delivery system, where use of a dry aprotic solvent results in conditions similar to solid state stability.