Pulmonary vein isolation (PVI) using cryoenergy is safe and efficient for treatment of atrial fibrillation (AF). Pre-existing upper gastrointestinal (GI) pathologies have been shown to increase the risk for AF. Therefore, this study aimed at assessing incidental pathologies of the upper GI tract in patients scheduled for PVI and to analyse the impact of patients’ characteristics on PVI safety outcome. In 71 AF patients, who participated in the MADE-PVI trial, oesophagogastroduodenoscopy and endosonography were prospectively performed directly before and the day after PVI to assess pre-existing upper GI pathologies and post-interventional occurrence of PVI-associated lesions. Subgroup analysis of the MADE-PVI trial identified clinically relevant incidental findings in 53 patients (74.6%) with age > 50 years being a significant risk factor. Pre-existing reflux oesophagitis increased risk for PVI-associated mediastinal oedema, while patients already treated with proton pump inhibitors (PPI) had significantly fewer mediastinal oedema. Our results suggest that AF patients with pre-existing reflux oesophagitis are at higher risk for PVI-associated mediastinal lesions, which is decreased in patients with constant PPI-treatment prior to PVI. Since PVI-associated mediastinal lesions are regarded as surrogate parameter for an increased risk of the fatal complication of an oesophago-atrial fistula, our findings hint at a beneficial effect of pre-interventional prophylactic PPI-treatment to reduce risk for PVI-associated complications.