This dataset contains raw LC–MS/MS data and associated search results generated for the identification and characterization of proteome-derived cyclic peptides produced via ortho-phthalaldehyde (OPA)-mediated macrocyclization. Cysteine-containing peptides derived from human proteome digests were selectively enriched and subjected to OPA-mediated intramolecular cyclization under mild aqueous conditions. The resulting cyclic peptide libraries were analyzed by high-resolution Orbitrap mass spectrometry. MS/MS data were processed using pLink3 with customized modification parameters corresponding to OPA-mediated cyclization products. The dataset includes raw Thermo .raw files and associated search results supporting the systematic annotation of cyclic peptide topologies and fragmentation behavior. These data support the development of a rule-based automated MS/MS annotation pipeline and the identification of functional cyclic peptide binders targeting human immunoglobulin G (IgG).