This study describes the clinical presentations and histology of surgical biopsy-proven nonspecific interstitial pneumonia (NSIP) in 6 patients with clinical and radiologic progression, resulting in the need for rebiopsy or lung transplantation. The majority of patients were middle-aged women (F/M=5) with shortness of breath, dyspnea on exertion, and dry cough. Three had evidence of autoimmune disease/phenomena. High-resolution computerized tomographic scans revealed bilateral ground-glass infiltrates without honeycomb change in 4 of 6 cases; over time (16 to 115 mo), 5 of the 6 cases developed subpleural honeycomb change. Histologic examination of the initial biopsy showed fibrotic variant NSIP in 5 cases and cellular variant NSIP in 1 case. At repeat biopsy and/or transplantation, the 5 cases of fibrotic NSIP showed morphologic features of usual interstitial pneumonia, whereas the cellular case showed fibrotic variant NSIP. The potential pathophysiologic explanation for such a change is discussed.