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Background Malignant pleural effusions continue to be a common problem in patients with metastatic disease, leading to a significant reduction in quality of life with progressive dyspnea, dry cough, chest pain and reduced physical activity. This study was conducted to compare the efficacy, safety, and outcome of Talc Powder Pleurodesis (TPP) with Povidone-iodine Pleurodesis (PIP) through a chest drain as a palliative preventive treatment of recurrent malignant pleural effusion. Methods A total of 39 neoplastic patients with recurrent malignant pleural effusion were enrolled in a prospective randomized trial. Twenty-one patients received Talc pleurodesis (group A), and eighteen patients (group B) received Povidone-iodine pleurodesis. The continuous variables were expressed as mean values ± standard deviation (SD) and compared using the unpaired t-test. The discrete variables were expressed as percentage and compared using the chi-square test (χ2) test. p-values of less than 0.05 were considered significant. Results Our study included 11 males and 28 females, the mean age was (71.0 ± 5.0) years for group A and (70.9 ± 5.1) years for group B (non-significant). Post-procedure analgesic requirements were recorded in both groups. Four patients in each group had fever (>38°C) within 48 hours of the procedure. Both groups achieved good symptomatic relief. There were no in-hospital deaths. The mean post-procedure hospital stay was (4.7 ± 1.2) days for group A and (4.2 ± 1.0) for group B (non-significant). At follow-up recurrence of significant pleural effusion requiring intervention was noted in four and five patients in group A and group B, respectively (non-significant difference). Conclusion Povidone-iodine pleurodesis can be considered as a good alternative to Talc pleurodesis for recurrent malignant pleural effusion. The drug is available, cost effective, safe and can be administered through an intercostal drain and repeated if necessary.