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Rationale: Evaluation of a pleural effusion has historically focused on establishing a single etiology. Pleural fluid may accumulate through multiple pathophysiological processes. The prevalence of multiple causes for pleural effusions has not been established. The identification of contributing processes may improve clinical outcomes. Objectives: The objective of this prospectively collected case series was to establish the prevalence and nature of multiple etiologies for a unilateral pleural effusion. Methods: Consecutive patients presenting with an undiagnosed unilateral pleural effusion were recruited at a tertiary pleural center. Patients underwent a comprehensive structured diagnostic clinical evaluation and were followed up for a minimum of 12 months, after which one or more diagnoses were recorded independently by two experienced clinicians. Measurements and Main Results: One hundred thirty patients were recruited to the study over a 24-month period, and 126 patients completed follow up. Altogether, 88 patients (70%) had a single cause for their pleural effusion, and 38 (30%) had multiple causes. Serum N-terminal pro-brain natriuretic peptide (NT-pro BNP) greater than or equal to 1,500 pg/ml was predictive of multiple etiologies. NT-pro BNP had a sensitivity and specificity of 79 and 88%, respectively, for establishing heart failure as a primary or contributory cause. Thirteen patients with a malignant pleural effusion also had an NT-pro BNP greater than or equal to 1,500 pg/ml. Conclusions: This study is the first to estimate the prevalence of more than one identifiable cause for a unilateral pleural effusion. Out of 130 study subjects, 38 (30%) had multiple causes for an effusion. The identification of multiple pathologies underlying an accumulation of fluid in the pleural space may be important in determining optimum treatment and improving patients' symptoms.