Rationale and objectives: To assess the use of chest digital radiograph (DR) assisted with a real-time interactive pulmonary nodule analysis system in large population lung cancer screening. Materials and methods: 346 DR/CR patient studies with corresponding CT images were selected from 12,500 patients screened for lung cancer from year 2007 to 2009. Two expert chest radiologists established CT-confirmed Gold Standard of nodules on DR/CR images with consensus. These cases were read by eight other chest radiologists (participating radiologists) first without using a real-time interactive pulmonary nodule analysis system and then re-read using the system. Performances of participating radiologists and the computer system were analyzed. Results: The computer system achieved similar performance on DR and CR images, with a detection rate of 76% and an average FPs of 2.0 per image. Before and after using the computer-aided detection system, the nodule detection sensitivities of the participating radiologists were 62.3% and 77.3% respectively, and the Az values increased from 0.794 to 0.831. Statistical analysis demonstrated statically significant improvement for the participating radiologists after using the computer analysis system with a P-value 0.05. Conclusion: The computer system could help radiologists identify more lesions, especially small ones that are more likely to be overlooked on chest DR/CR images, and could help reduce inter-observer diagnostic variations, while its FPs were easy to recognize and dismiss. It is suggested that DR/CR assisted by the realtime interactive pulmonary nodule analysis system may be an effective means to screen large populations for lung cancer. (C) 2011 Elsevier Ireland Ltd. All rights reserved.