BACKGROUND Pneumonectomy in the adult patient is associated with a mortality of 1-9%. Death is often due to post pneumonectomy pulmonary oedema (PPPO). The use of balanced chest drainage system (BCD) in the setting of post pneumonectomy has been reported to be of benefit in the prevention of PPPO. This study seeks to compare the incidence of PPPO in patients who underwent pneumonectomy and whose empty pleural space was managed either with CRD or BCD. METHODS This retrospective observational cohort study involved 98 patients who were operated on by one surgeon at Liverpool Hospital, Sydney, Australia from 1997 to 2019. The patients were divided into two groups according to the era in which they had their pneumonectomy. Group 1 consisted of 18 patients managed with clamp-release drainage between 1997 and 2002. Group 2 consisted of 80 patients managed with balanced chest drainage between 2003 and 2019. The primary outcomes of interest were the development of PPPO and death. Demographic and clinico-pathological variables between the groups were compared including whether the phrenic nerve was sacrificed, volume of infused intraoperative fluid, duration of single lung ventilation, intraoperative tidal volumes, agents of anaesthetic induction and maintenance, mean urine output in the first 4 postoperative hours, institution of a postoperative 1.5 L fluid restriction, total chest drainage, day of chest drain removal, presence of radiological postoperative mediastinal shift, post-pneumonectomy pulmonary oedema and death. Group characteristics were compared using t-test and chi-squared for continuous and categorical variables respectively. Univariate and multivariate analysis was also undertaken using the Firth method of logistic regression for rare occurrences in a stepwise fashion. RESULTS Through univariate analysis, balanced chest drainage, postoperative fluid restriction and intraoperative fluid infusion showed significant effect on PPPO. Through multivariate analysis, balanced chest drainage was found to have independent protective value for PPPO and mortality. CONCLUSIONS Compared with clamp-release drainage, balanced chest drainage results in a lower incidence of post-pneumonectomy pulmonary oedema and death.