Objective: Whether patients with venous thromboembolism (VTE) receive targeted treatment or not, their mortality rates remain relatively high. Common risk factors for VTE include tumors, trauma, obesity, infection, and gene mutations related to the coagulation/anticoagulation system. However, research on the relationship between non-coagulation/anticoagulation system gene mutations and VTE is currently insufficient. Methods: This study retrospectively collected clinical data from 123 patients in the Department of Critical Care Medicine at Nanjing Jiangning Hospital from June 1, 2023, to December 31, 2024. Through univariate and multivariate analyses, risk factors for VTE in critically ill patients were identified, and a risk prediction model was constructed. Results: The proportion of patients carrying the ALDH2*2 genotype was higher in the VTE group than in those with the ALDH2*1 genotype (21.3% vs 7.9%, P = 0.032). Patients carrying the ALDH2*2 genotype had a 6.553-fold increased risk of developing VTE compared to those with the ALDH2*1 genotype. Patients with a history of diabetes had an 11.491-fold increased risk of VTE compared to those without diabetes, while patients with a history of smoking had a 39.302-fold increased risk compared to non-smokers. For each additional year of age, the risk of VTE increased by 12.5%. For each one-unit increase in left ventricular shortening fraction, the risk of VTE decreased by 37.4%. Conclusion: Mutation of the mitochondrial metabolic enzyme ALDH2 is a risk factor for VTE in critically ill patients and may represent a novel pathway for VTE prevention in this population.