Successful weaning from extracorporeal membrane oxygenation (ECMO) does not necessarily imply patient survival. We retrospectively analyzed 441 patients with acute respiratory failure from 16 hospitals in South Korea who underwent ECMO from January 2012 to December 2015. We evaluated the clinical factors associated with mortality after successful weaning from ECMO. Of all 441 patients, 245 (55.6%) were successfully weaned from ECMO. The majority of patients were initially supported with veno-venous ECMO (86.9%). Among those, 182 patients (41.3%) were discharged from hospital. Only 165 (37.4%) were alive after 6 months. Most cases of death occurred within the first month after weaning from ECMO (65%), and the most frequent reason for death was sepsis (76.2%). In the multivariate Cox regression analysis, patient age (per 10 years) (hazard ratio [HR] = 1.34, 95% CI = 1.12-1.61; p = 0.001), sequential organ failure assessment score (HR = 1.07, 95% CI = 1.02-1.13; p = 0.010), steroid (HR = 2.38, 95% CI = 1.27-4.45; p = 0.007), interstitial lung disease (HR = 1.20, 95% CI = 1.05-1.36; p = 0.006), and ECMO duration (per day) (HR = 1.02, 95% CI = 1.01-1.04; p < 0.001) were associated with the in-hospital mortality after weaning from ECMO. Furthermore, age (per 10 years) (HR = 1.45, 95% CI = 1.24-1.71; p < 0.001), steroid (HR = 2.19, 95% CI = 1.27-3.78; p = 0.005), and interstitial lung disease (HR = 1.16, 95% CI = 1.02-1.31; p = 0.021) were significantly associated with 6 month mortality. The prognosis after weaning from respiratory ECMO might be related to baseline conditions affecting the reversibility of the primary lung disease and to acquired infections.