BACKGROUND Malignant pleural effusion (MPE) is associated with a significant impact on health-related quality of life. Palliative interventions abound, with varying costs and degrees of invasiveness. We examined the relative cost-utility of 5 therapeutic alternatives for MPE among adults. METHODS Original studies investigating the management of MPE were extensively researched, and the most robust and current data particularly those from the TIME2 trial were chosen to estimate event probabilities. Medicare data were used for cost estimation. Utility estimates were adapted from 2 original studies and kept consistent with prior estimations. The decision tree model was based on clinical guidelines and authors' consensus opinion. Primary outcome of interest was the incremental cost-effectiveness ratio for each intervention over a less effective alternative over an analytical horizon of 6 months. Given the paucity of data on rapid pleurodesis protocol, a sensitivity analysis was conducted to address the uncertainty surrounding its efficacy in terms of achieving long-term pleurodesis. RESULTS Except for repeated thoracentesis (RT; least effective), all interventions had similar effectiveness. Tunneled pleural catheter was the most cost-effective option with an incremental cost-effectiveness ratio of $45,747 per QALY gained over RT, assuming a willingness-to-pay threshold of $100,000/QALY. Multivariate sensitivity analysis showed that rapid pleurodesis protocol remained cost-ineffective even with an estimated probability of lasting pleurodesis up to 85%. CONCLUSIONS Tunneled pleural catheter is the most cost-effective therapeutic alternative to RT. This, together with its relative convenience (requiring neither hospitalization nor thoracoscopic procedural skills), makes it an intervention of choice for MPE.