This study was conducted to determine if pleural effusion size affects ventilation/perfusion (V/Q) scan interpretation algorithms for acute pulmonary embolus (PE). METHODS Retrospective analysis identified 163 consecutive patients undergoing angiography for PE with radiographic evidence for pleural effusion. V/Q scanning was performed in 94 (58%) of cases and reported using original Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) criteria. Effusions were classified as small, large and/or bilateral. Radiographic and scintigraphic results were compared with regard to size and location of abnormalities. RESULTS Of the 163 patients, 57 (35%) had angiographically-proven PE, 77 (47%) had at least one large pleural effusion and 86 (53%) had a small effusion; 33 (43%) with large effusions and 24 (28%) with small effusions had emboli at angiography. Thirty-six of 119 patients (30%) with clear chest radiographs (a control group) had PE. Thus, large effusions were associated with a higher incidence of PE than those with small effusions or clear lungs (p < 0.05). Of those with V/Q scanning, 26 of 94 (28%) had a solitary large effusion, with 12 (46%) positive for emboli. V/Q-matched abnormalities limited to effusion size were found in 16 with a solitary large effusion and 10 with a solitary small effusion. In both groups, 50% were angiographically positive for emboli. Twenty-three (66%) of 35 with bilateral effusions had corresponding V/Q-matched defects at one (n = 11) or both (n = 12) lung bases, and 9 (39%) were positive for emboli. In total, 45% with a V/Q-matched defect of equivalent size to the effusion were angiographically positive for PE. CONCLUSIONS Pulmonary emboli are associated with pleural effusions of all sizes. Matched V/Q defects corresponding to radiographically-evident pleural effusions are of intermediate probability for PE. Thus, revision of the traditional lung scan interpretive criteria based upon pleural effusion size is not warranted.