Salmon calcitonin (sCT), a 32-amino-acid peptide, is the active component in many pharmaceuticals used for the management of bone diseases. The degradation pathways of sCT were determined, and the structures of the major degradation products were identified. Aqueous solutions of sCT at pH values of 3, 4, 5, and 6 were degraded, and the major degradation products were detected using reversed phase and size-exclusion high-performance liquid chromatography (HPLC). The degradation rate and pathways of sCT are strongly dependent on pH in the pH range between 3 and 6. The major degradation products were isolated by semipreparative HPLC and identified using a variety of spectroscopic and bioanalytical techniques. The results show that sCT can undergo hydrolyses resulting in cleavage of the 1-2 amide bond and deamidation of the Gln14 and Gln20 residues, sulfide exchange that leads to an unusual trisulfide derivative, and dimerization to reducible and nonreducible dimers. The mechanisms for the pathways can be rationalized from known degradation pathways of peptide and proteins.