OBJECTIVE To assess the sensitivity of high-resolution chest computed tomography (HRCT) in detecting idiopathic pulmonary fibrosis proved by biopsy specimen. To determine the degree of physiologic and pathologic abnormalities in patients with idiopathic pulmonary fibrosis who have a false-negative HRCT. METHODS Prospective 2-year study. METHODS Tertiary care university hospital. METHODS All patients with dyspnea and suspected interstitial lung disease referred to the University of Michigan for enrollment in the Idiopathic Pulmonary Fibrosis Specialized Center of Research (SCOR) protocol were included; 25 underwent open lung biopsy and formed the final study group. METHODS All patients underwent physiologic (pulmonary function, gas exchange, and exercise testing), radiologic (chest x-ray film and HRCT), and pathologic assessments (bronchoscopic and open lung biopsy). The results of HRCT were prospectively compared with results of standard pulmonary function tests, cardiopulmonary exercise testing, and open lung biopsy. RESULTS Of 25 patients who had both HRCT and open lung biopsy, 3 patients (12%) had HRCTs that demonstrated no evidence of interstitial lung disease. These three patients had less severe disease based on clinical, radiographic, and physiologic (CRP) scores, gas exchange abnormalities, and pathologic scoring of open lung biopsy specimens, compared with those with an abnormal HRCT. CONCLUSIONS We conclude that in the evaluation of patients with dyspnea and abnormal results of pulmonary function studies, a normal HRCT does not exclude early and clinically significant interstitial lung disease. In our patient population, physiologic testing was more sensitive than HRCT in detecting mild abnormalities in patients with idiopathic pulmonary fibrosis proved by biopsy specimen.