Background There is a paucity of newer studies focusing on survival patterns in the era of targeted pulmonary vasodilators in Eisenmenger syndrome (ES). We aimed to study the survival pattern, mortality predictors and outcome of targeted pulmonary vasodilator therapy in patients with ES. Methods This was a single-centre retrospective observational study of patients treated between January 2000 and January 2020. Consecutive patients with clinical and echo- cardiographic and/or cardiac catheterization diagnoses of ES were included in the study. Shunt types were classified into pre-tricuspid shunts, post-tricuspid shunts and complex lesions. Clinical outcomes and treatment data of all patients were assessed. Results Of 206 patients, 139 were female with a mean (SD) age of 23.4 (14.3) years. Pre-tricuspid shunts were the most common shunt type, with atrial septal defect being the most common anatomical defect. During a mean (SD) follow-up of 7.1 (6.2) years, a significant decline in mean resting systemic saturation and WHO functional class on follow-up was observed. Atrial arrhythmias and right ventricular dysfunction were the most common in pretricuspid shunt lesions. ES secondary to complex defects had the worst prognosis with early attrition. Survival patterns were equally poor in complex defects and pre-tricuspid defects after the onset of Eisenmenger physiology. Targeted pulmonary vasodilator therapy was associated with better survival, irrespective of monotherapy or dual therapy. Congestive heart failure was the most common cause of death. Survival at 5 and 10 years in the disease modifier treatment group was 84% and 69% while in the treatment naïve group was 66% and 44%. Resting systemic saturation <80% on follow-up, the presence of atrial arrhythmias and the absence of disease-targeted therapy were independently associated with mortality. Conclusion The long-term survival of patients with ES remains poor in the era of targeted pulmonary vasodilator therapy. ES resulting from complex cyanotic congenital heart diseases has the worst survival outcomes. Although pretricuspid shunt ES patients survived longer, they tended to decompensate at lower mean pulmonary artery pressure than all other subgroups with ES. Targeted pulmonary vasodilator therapy may be associated with improved functional class and survival benefits in ES.