OBJECTIVE To assess the diagnostic yield of computed tomography (CT)-guided percutaneous cutting needle biopsy of diffuse pleural thickening. METHODS In 42 consecutive adult patients with diffuse pleural disease seen, 45 CT-guided percutaneous biopsies were performed with an 18-gauge cutting needle powered by a hand-held, spring-operated biopsy instrument. Results were assessed retrospectively. RESULTS Sufficient pleural tissue for histologic diagnosis was obtained in 42 of the 45 biopsies, with a correct histologic diagnosis made in 39 of the 42 specimens. Specificity and sensitivity for helping differentiate malignant from benign disease were 100% and 83%, respectively. Positive and negative predictive values were 1.0 and 0.60, respectively. By combining findings at biopsy and at CT (presence or absence of pleural thickness greater than 1 cm, mediastinal-circumferential involvement, irregular contour), sensitivity and negative predictive values reached 100% and 1.0, respectively. CONCLUSIONS Combined findings of CT-guided percutaneous cutting needle biopsy and CT are useful in first-line investigation of diffuse pleural thickening.