Biopsy by video-assisted thoracoscopic surgery (VATS) for interstitial pneumonia allows collection of samples sufficient for accurate histologic diagnosis. Although VATS is relatively safe, several reports have suggested that surgical lung biopsy may be a risk factor for acute exacerbation of idiopathic pulmonary fibrosis (IPF). We retrospectively reviewed data on the 113 cases that underwent biopsy by VATS to diagnose diffuse parenchymal lung disease in our department between 1994 and 2006, and analyzed its complications, in particular, risk of acute exacerbation of IPF. As the final diagnosis, idiopathic interstitial pneumonia was most frequent, involving 52 cases, of which IPF was most frequently found followed by nonspecific interstitial pneumonia and cryptogenic organizing pneumonia, in that order. Among our cases, there were 2 deaths after VATS (mortality rate, 1.8%), and both were IPF cases with acute exacerbation. When examining clinical markers in the 2 fatal IPF cases with acute exacerbation, we found that the percentage of predicted forced vital capacity was 55 or lower, percentage of predicted carbon monoxide diffusing capacity was 40 or lower, serum interstitial pneumonia markers KL-6 and SP-D were elevated, intraoperative inhalation of 100% O2 was 80 minutes or longer, and postoperative thoracic drainage was required for 10 days or longer. Although acute exacerbations of IPF seem to occur at any time during the course of disease, it is important to be aware of the possibility of acute exacerbation of IPF after VATS.