BACKGROUND: Perioperative management to maintain intraoperative haemodynamic stability is crucial during surgical treatment of pheochromocytomas and paragangliomas (PPGLs). Although ~70% of PPGLs carry pathogenic variants (PVs) in susceptibility genes, whether intraoperative haemodynamic instability (IHI) is associated with genetic background remains unclear. This study aimed to analyse IHI in patients with PPGL due to PVs in different genes. MATERIALS AND METHODS: This retrospective study recruited 756 patients with abdominal PPGL from two tertiary care centres. Clinical information including sex, age, catecholamine-associated signs and symptoms (CAS), tumour location and size, biochemistry, and perioperative characteristics were collected. Genetic mutations were investigated using next-generation sequencing. RESULTS: Among the 671 patients included in the analysis, 61.8% (415/671) had IHI. IHI was significantly associated with genetic background in patients with PPGL. Most (80.9%, 89/110) patients with PPGL due to PVs in HRAS suffered IHI. In contrast, only half (31/62) of patients with PPGL due to PVs in VHL had IHI. In the multivariate regression analysis, compared to those with negative genetic testing results, patients with PPGL due to PVs in HRAS (OR 3.82, 95% CI 2.187-6.679, P <
0.002), the other cluster 2 genes (OR 1.95, 95% CI 1.287-2. 569, P <
0.05), and cluster 1 genes other than VHL (OR 2.35, 95% CI 1.338-4.111, P <
0.05) were independent risk factors for IHI, while PVs in VHL was not independent risk factor (OR 1.09, 95% CI 0.605-1.953, P ≥0.05). In addition, age at diagnosis of the primary tumour, presenting of CAS, and tumour size were identified as independent factors for IHI. The nomogram illustrated that genetic background as sharing the largest contribution to IHI, followed by tumour size, age, and presentation of CAS. CONCLUSION: IHI is associated with the genetic background in patients with PPGL. The perioperative management of patients with PPGL can be personalised according to their genetic backgrounds, tumour size, age, and presentation of CAS.