Background: There is sparse evidence in the literature in relation to the nature and causes of pleural effusion among Australian Indigenous population. Aim: To investigate the clinical and demographic characteristics of adult indigenous patients presenting with pleural effusion in the Northern Territory of Australia. Methods: In this retrospective study, indigenous and non-indigenous adults diagnosed to have pleural effusion over a 2-year study period were included for comparative analysis. Results: Of the 314 patients, 205 (65%) were non-indigenous and 52% were male. In comparison with non-indigenous patients, the indigenous patients were younger (50 years (interquartile range (IQR) 39–60) vs 63 years (IQR 52–72); P < 0.001), female (61% vs 41%; P = 0.001), had a higher prevalence of renal and cardiovascular disease and tended to have exudative effusion (93% vs 76%; P = 0.032). Infections were judged to be the most common cause of effusion in both groups, more so among the indigenous cohort. Effusion secondary to renal disease was higher (13% vs 1%; P < 0.001) among Australian Indigenous patients, but in contrast, malignant effusions were higher (13% vs 4%; P = 0.004) among non-indigenous patients. Length of hospital stay was longer for indigenous patients (P = 0.001), and a greater proportion received renal dialysis (13% vs 1%; P < 0.001). Intensive care unit admission rates were higher with infective aetiology of pleural effusion (82% vs 53% indigenous and 44% vs 39% non-indigenous respectively). Re-presentations to hospital were higher among indigenous patients (46% vs 33%; P = 0.046) and were associated with renal and cardiac disease and malignancy in non-indigenous patients. Conclusion: There are significant differences in the way pleural effusion manifests among Australian Indigenous patients. Understanding these differences might facilitate approaches to management and to implementation of strategies to reduce morbidity and mortality in this population.