Background: Alcohol dependence is an overall health-related challenge; however, the specific mechanisms underlying alcohol dependence remain unclear. Serine proteinase inhibitor A3 (SERPINA3) plays crucial roles in multiple human diseases; however, its role in alcohol dependence clinical practice has not been confirmed.Methods: We screened Gene Expression Omnibus (GEO) expression profiles, and identified differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks were generated using STRING and Cytoscape, and the key clustering module was identified using the MCODE plugin. SERPINA3-based target microRNA prediction was performed using online databases. Functional enrichment analysis was performed. Fifty-eight patients with alcohol dependence and 20 healthy controls were recruited. Clinical variables were collected and follow-up was conducted for 8 months for relapse.Results:SERPINA3 was identified as a DEG. ELANE and miR-137 were identified after PPI analysis. The enriched functions and pathways included acute inflammatory response, response to stress, immune response, and terpenoid backbone biosynthesis. SERPINA3 concentrations were significantly elevated in the alcohol dependence group than in healthy controls (P < 0.001). According to the median value of SERPINA3 expression level in alcohol dependence group, patients were divided into high SERPINA3 (≥2677.33 pg/ml, n = 29) and low SERPINA3 groups (<2677.33 pg/ml, n = 29). Binary logistic analysis indicated that IL-6 was statistically significant (P = 0.015) Kaplan-Meier survival analysis did not indicate any difference in event-free survival between patients with low and high SERPINA3 levels (P = 0.489) after 8 months of follow-up. Receiver characteristic curve analysis revealed that SERPINA3 had an area under the curve of 0.921 (P < 0.0001), with a sensitivity and specificity of 93.1 and 80.0%, respectively. Cox regression analysis revealed that aspartate transaminase level was a negative predictor of relapse (β = 0.003; hazard ratio = 1.003; P = 0.03).Conclusions:SERPINA3 level was remarkably elevated in patients with alcohol dependence than healthy controls, indicating that SERPINA3 is correlated with alcohol dependence. However, SERPINA3 may not be a potential predictive marker of relapse with patients in alcohol dependence.