MOTIVATION: Adverse drug reactions (ADRs) are a major issue in drug development and clinical pharmacology. As most ADRs are caused by unintended activity at off-targets of drugs, the identification of drug targets responsible for ADRs becomes a key process for resolving ADRs. Recently, with the increase in the number of ADR-related data sources, several computational methodologies have been proposed to analyze ADR-protein relations. However, the identification of ADR-related proteins on a large scale with high reliability remains an important challenge. RESULTS: In this article, we suggest a computational approach, Large-scale ADR-related Proteins Identification with Network Embedding (LAPINE). LAPINE combines a novel concept called single-target compound with a network embedding technique to enable large-scale prediction of ADR-related proteins for any proteins in the protein-protein interaction network. Analysis of benchmark datasets confirms the need to expand the scope of potential ADR-related proteins to be analyzed, as well as LAPINE's capability for high recovery of known ADR-related proteins. Moreover, LAPINE provides more reliable predictions for ADR-related proteins (Value-added positive predictive value = 0.12), compared to a previously proposed method (P < 0.001). Furthermore, two case studies show that most predictive proteins related to ADRs in LAPINE are supported by literature evidence. Overall, LAPINE can provide reliable insights into the relationship between ADRs and proteomes to understand the mechanism of ADRs leading to their prevention. AVAILABILITY AND IMPLEMENTATION: The source code is available at GitHub (https://github.com/rupinas/LAPINE) and Figshare (https://figshare.com/articles/software/LAPINE/21750245) to facilitate its use. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.