<p>Antipsychotic-related erectile dysfunction (APRED) may represent a clinically significant yet poorly understood biological vulnerability in a subset of male patients with schizophrenia, rather than a simple pharmacological side effect. Identifying molecular mechanisms associated with APRED may facilitate early identification of susceptible individuals and inform precision treatment strategies. In a case–control design, 66 male patients with schizophrenia receiving risperidone monotherapy were stratified into APRED and non-APRED groups based on nocturnal penile tumescence monitoring. Label-free quantitative serum proteomics was performed to identify differentially expressed proteins (DEPs). Multivariate statistical analyses, functional enrichment, and protein–protein interaction (PPI) network analyses were conducted to characterize the molecular landscape associated with APRED. A total of 473 DEPs were identified between the APRED and non-APRED groups, with principal component analysis demonstrating clear group separation. Functional annotation showed significant enrichment of pathways related to immune and inflammatory responses, calcium signaling, and extracellular matrix organization. PPI network analysis of the top 40 DEPs identified 10 hub proteins, including RYR3, PRKCA, and KRT18, with RYR3 emerging as a central regulatory node linking calcium signaling and immune-related pathways. These findings identify a distinct serum proteomic signature associated with APRED in schizophrenia. The results are consistent with a hypothesized cascade characterized by gene expression reprogramming, immune and calcium signaling disruption, and subsequent structural–functional imbalance. Collectively, this study suggests that APRED may represent a peripheral manifestation of a schizophrenia-related biological subtype with intrinsic vulnerability along an immune–calcium signaling axis, providing a potential framework for early risk stratification and precision psychopharmacological management.</p>