Objective: To investigate the association between plasma hypoxia-inducible factor-1α(HIF-1α) and moderate-to-large residual shunt(MLRS) after percutaneous patent foramen ovale(PFO) closure in patients with migraine and PFO. Methods: This prospective study included 45 migraine patients who underwent PFO closure at the Affiliated Hospital of Nantong University from August 2023 to August 2024. Patients were divided into MLRS and non-MLRS groups based on the presence or absence of MLRS. Clinical data and plasma HIF-1α levels were collected and compared before surgery, and 6 and 12 months after surgery. Multivariate logistic regression was used to identify potential factors for MLRS at 6 and 12 months. Receiver operating characteristic(ROC) curves evaluated predictive performance, and generalized estimating equation(GEE) assessed the interaction of HIF-1α with both antithrombin Ⅲ(AT-Ⅲ) and the neutrophil-to-lymphocyte ratio(NLR). Results: Plasma HIF-1α levels at 6 and 12 months postoperatively were significantly lower than preoperative levels(P < 0.01). Preoperative HIF-1α levels were significantly higher in the MLRS group than in the non-MLRS group at both follow-up time points(P < 0.05). Multivariate logistic regression showed that preoperative HIF-1α was a potential factor associated with MLRS at 6 and 12 months(P < 0.05). Decreased preoperative AT-Ⅲ levels were correlated with an increased risk of MLRS at 6 months postoperatively(P < 0.05), while elevated preoperative NLR levels were associated with an increased risk of MLRS at 12 months(P < 0.05).After Bootstrap correction, ROC analysis demonstrated that the area under curve(AUC) values of preoperative HIF-1α for predicting MLRS at 6 and 12 months were 0.823 and 0.825, respectively. The AUC for HIF-1α combined with AT-Ⅲ was 0.953(6 months), and with NLR was 0.937(12 months)(all P < 0.05). GEE revealed a significant association between HIF-1α and NLR(P < 0.05). Conclusion: Plasma HIF-1α levels show sustained decline after PFO closure. Preoperative plasma HIF-1α is a potential factor associated with postoperative MLRS, and its combination with AT-Ⅲ(at 6 months) and NLR(at 12 months) shows preliminary discriminative performance, respectively.