A 69-year-old man was started on pirfenidone (600 mg/day) for progressive dyspnea due to IPF. He had a 51 pack-year smoking history, but no occupational exposure to inhaled irritants. He had been taking omeprazole and mosapride to treat reflux esophagitis for at least 1 year. The patient had no history of allergies, respiratory disease other than IPF, or pleural disease. After 2 weeks of pirfenidone treatment, a mild elevation of serum eosinophils (380 /muL) was noted. After 5 weeks of treatment, the pirfenidone dose was increased to 1,200 mg/day. After 7 weeks of treatment, he presented with worsening left-sided chest pain and was admitted to the hospital. His temperature was 36.8C, and his peripheral oxygen saturation (SpO2), as measured by pulse oximetry, was 90% in ambient air. During a physical examination, auscultation revealed fine crackles in the chest. The laboratory data on admission revealed elevated eosinophils (538/muL) and C-reactive protein (5 mg/dL), and an interferon-gamma release assay (QuantiFERON(R)-TB gold in tube) was positive. A parasitic disease was ruled out because the patient was negative for ova and parasites and showed a normal serum immunoglobulin (Ig)E level. The results of a physical examination and his serum levels of autoantibodies including antinuclear antibody (x20, nucleolar pattern) did not suggest collagen vascular disease. Chest radiography (Fig. 1) and computed tomography (CT) (Fig. 2) showed left pleural effusion, reticular opacities with traction bronchiectasis and honeycombing in the lower lobes. An analysis of the pleural fluid obtained in the first thoracentesis showed an exudative pattern with elevated lymphocytes (68%) and eosinophils (25%), and slightly elevated levels of adenosine deaminase (37.9 IU/L), without malignant cells or elevated tumor marker levels [carcinoembryonic antigen (CEA), 3.1 ng/mL; cytokeratin 19 fragment (CYFRA), 1.5 ng/mL]. These investigations revealed EPE with a usual interstitial pneumonia pattern and tuberculous pleurisy and malignant disease could not be excluded. Medical thoracoscopy showed diffuse pleural thickening with multiple translucent nodules and adhesions in the parietal pleura and diaphragm (Fig. 3). A histopathological examination of the nodule in the diaphragm revealed lymphoid follicles and the massive infiltration of eosinophils, lymphocytes, and plasma cells, without cancer cells or granuloma (Fig. 4). Cultures of sputum, pleural effusion and specimens from the parietal pleura were negative for bacteria and mycobacteria. Based on these results, we suspected pirfenidone-induced pleurisy. As a result, pirfenidone was discontinued and the patient's chest pain and serum eosinophilia gradually improved and finally resolved. The marked spontaneous resolution of the pleural effusion was observed at eight weeks after the suspension of pirfenidone and without any additional treatment. The patient died of the progression of IPF with bacterial pneumonia 3 years later. During that time, pleural effusion did not recur, nor did serum eosinophilia or other possible etiologies of EPE, which included tuberculosis, malignancy, parasitic disease and collagen-vascular disease.