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Background and Aims Chronic post-surgical pain (CPSP) is one of the most common surgical-related complications that significantly impacts patients‘ quality of life, while studies exploring the underlying genetics remains limited and controversial.Methods In a total of 17,025 individuals from the Chinese Surgery and Anaesthesia cohort (CSAC), we used Brief Pain Inventory questionnaire to measure the longitudinal pain intensity after surgery and defined CPSP either as a dichotomous or continuous trait across various surgical sites (i.e., abdomen, thorax, head and neck, limbs and body surfaces), as well as in the context of a prolonged pain trajectory (i.e., persistent pain intensity across multiple post-surgery follow-up points). Genome-wide association (meta-) analyses were then conducted among 9,022 individuals with genotyping data.Results We identified 16 independent genome-wide significant loci associated with different assessments of CPSP, respectively. Multiple approaches including gene mapping, annotation, and multi-omics colocalization prioritized several potential risk genes, such as ASTN1, RSU1, and C1QL3 that are involved in neuronal migration, ERK/MAPK signaling, and synaptic function. The SNP-based narrow-sense heritability was estimated as 13.7% (5.1%-22.4%) for CPSP by numeric definition. Polygenic risk scores of post-traumatic stress disorder, pain all over the body, multisite chronic pain, and opioid dependence were positively associated with CPSP, either at specific surgical sites or in general, at a nominal significance level.Abstract OP13 Figure 1Overview of the study designConclusions This largest available GWAS advance our understanding of the genetic predisposition to and pathogenesis of CPSP, which could vary across different surgical sites. Focusing on homogenous subgroup may open new areas for therapeutic investigation.