Importance For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because theymay reduce pleurodesis efficacy. Smaller chest tubesmay be less painful than larger tubes, but efficacy in pleurodesis has not been proven. Objective To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. Design, Setting, and Participants A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. Interventions Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). Main Outcomes and Measures Pain while chest tubewas in place (0-to100-mmvisual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). Results Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8mmvs 22.1 mm; adjusted difference,-1.5 mm; 95%CI,-5.0 to 2.0 mm; P =.40), but the NSAID group required more rescue analgesia (26.3%vs 38.1%; rate ratio, 2.1; 95%CI, 1.3-3.4; P =.003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference,-3%; 1-sided 95%CI,-10% to; P =.004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0mmvs 26.8 mm; adjusted difference,-6.0 mm; 95%CI,-11.7 to-0.2 mm; P =.04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference,-6%; 1-sided 95%CI,-20% to P =.14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14%vs 24%; odds ratio, 1.91; P =.20). Conclusions and Relevance Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy.