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Introduction: Pathophysiology changes associated with pleural effusion, its drainage and factors governing symptom response are poorly understood. Our objective was to determine: 1) the effect of pleural effusion (and its drainage) on cardiorespiratory, functional and diaphragmatic parameters; and 2) the proportion as well as characteristics of patients with breathlessness relief post-drainage., Methods: Prospectively enrolled patients with symptomatic pleural effusions were assessed at both pre-therapeutic drainage and at 24-36 h post-therapeutic drainage., Results: 145 participants completed pre-drainage and post-drainage tests; 93% had effusions ≥25% of hemithorax. The median volume drained was 1.68 L. Breathlessness scores improved post-drainage (mean visual analogue scale (VAS) score by 28.0±24 mm; dyspnoea-12 (D12) score by 10.5±8.8; resting Borg score before 6-min walk test (6-MWT) by 0.6±1.7; all p<0.0001). The 6-min walk distance (6-MWD) increased by 29.7±73.5 m, p<0.0001. Improvements in vital signs and spirometry were modest (forced expiratory volume in 1 s (FEV 1 ) by 0.22 L, 95% CI 0.18-0.27; forced vital capacity (FVC) by 0.30 L, 95% CI 0.24-0.37). The ipsilateral hemi-diaphragm was flattened/everted in 50% of participants pre-drainage and 48% of participants exhibited paradoxical or no diaphragmatic movement. Post-drainage, hemi-diaphragm shape and movement were normal in 94% and 73% of participants, respectively. Drainage provided meaningful breathlessness relief (VAS score improved ≥14 mm) in 73% of participants irrespective of whether the lung expanded (mean difference 0.14, 95% CI 10.02-0.29; p=0.13). Multivariate analyses found that breathlessness relief was associated with significant breathlessness pre-drainage (odds ratio (OR) 5.83 per standard deviation (sd) decrease), baseline abnormal/paralyzed/paradoxical diaphragm movement (OR 4.37), benign aetiology (OR 3.39), higher pleural pH (OR per sd increase 1.92) and higher serum albumin level (OR per sd increase 1.73)., Conclusions: Breathlessness and exercise tolerance improved in most patients with only a small mean improvement in spirometry and no change in oxygenation. Breathlessness improvement was similar in participants with and without trapped lung. Abnormal hemi-diaphragm shape and movement were independently associated with relief of breathlessness post-drainage., Competing Interests: Conflict of interest: S. Muruganandan has nothing to disclose. Conflict of interest: M. Azzopardi has nothing to disclose. Conflict of interest: R. Thomas has nothing to disclose. Conflict of interest: D.B Fitzgerald has nothing to disclose. Conflict of interest: Y.J. Kuok has nothing to disclose. Conflict of interest: H.M. Cheah has nothing to disclose. Conflict of interest: C.A. Read has nothing to disclose. Conflict of interest: C.A. Budgeon has nothing to disclose. Conflict of interest: P.R. Eastwood has nothing to disclose. Conflict of interest: S. Jenkins has nothing to disclose. Conflict of interest: B. Singh has nothing to disclose. Conflict of interest: K. Murray has nothing to disclose. Conflict of interest: Y.C.G. Lee has served on the advisory board of CareFusion/BD Ltd and has previously led clinical trials for which Rocket Medical plc (UK) provided the drainage kits for study participants without charge, as well as providing an unrestricted educational grant to assist the running of the trial., (Copyright ©ERS 2020.)