The purpose of this study was to evaluate the accuracy of temporal subtraction with a commercially available computer-assisted diagnosis system for the detection of multifocal hazy pulmonary opacities on chest radiographs, which are sometimes difficult to detect directly on chest radiographs. Thirty healthy patients and 30 patients with new multifocal hazy pulmonary opacities that were confirmed by serial chest CT examinations were evaluated with and without temporal subtraction images. Chest radiographs were taken from either film-screen or digital radiography images and were digitized with a spatial resolution of 0.171 mm per pixel. Temporal subtraction images were produced by an iterative image-warping technique. We designed an observer performance study in which observers (six chest radiologists and four residents) indicated their confidence level for the presence or absence of hazy pulmonary opacities on two sets of images, current and previous radiographs only (set A), and current and previous radiographs with temporal subtraction images (set B). Receiver operating characteristic curves were generated. For chest radiologists, observer performance with set B (with temporal subtraction images; A(z) = 0.947) was superior to that with set A (without temporal subtraction images; A(z) = 0.916) (p < 0.05). For residents, no statistically significant difference was found between sets A and B. The temporal subtraction technique clearly improves diagnostic accuracy for the detection of multifocal hazy pulmonary opacities on chest radiographs, especially when the observers are experienced chest radiologists who have sufficient skill to evaluate the patient's condition as revealed on the images.