Objectives The purpose of this study is to compare the long‐term outcomes of patent foramen ovale (PFO) closure using angiography or transesophageal echocardiography as procedural guidance. Background The interventional treatment is emerging as a safe and efficient option for patients with high likelihood of PFO‐related cryptogenic stroke and high risk of recurrence. The “gold‐standard” guidance technique remains an issue. Methods Two cohorts of patients undergoing PFO closure for cryptogenic stroke in two catheterization laboratories of the same institution, using similar inclusion criteria but different guidance, were compared with propensity score matching. Results A total of 374 patients were enrolled, 161 in Angio‐group and 213 in Echo‐group. No difference was detected in the procedural complication rate. In Angio‐group, radiological exposure (P = .001) and 6‐month residual shunt (16.8% vs 8.0%, P = .015) were higher. After a mean follow‐up of 41 ± 30 months, 28 patients (7.5%) presented any adverse event (death, recurrent cerebral ischemia, device‐related complications, reintervention), with a higher rate in Angio‐group (13.0% vs 3.3%, P = .001), mainly due to repeated percutaneous intervention (10.6% vs 1.4%, P = .001). The results were confirmed after propensity score matching (118 patients/group). The rate of recurrent cerebral ischemia was 1.9% and was not significantly different in the two groups. Intra‐procedural guidance and atrial septum aneurysm were independent predictors of the composite primary endpoint (OR 1.2, P = .016). Conclusions The use of intra‐procedural transesophageal echocardiography (TEE) guidance for PFO closure allows lower residual shunt rate, radiological exposure, and adverse events, mainly driven by a significant reduction in percutaneous reintervention.