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Objectives: To evaluate the degree of variability in computer-assisted interpretation of low-dose chest CTs (LDCTs) among radiologists in a nationwide lung cancer screening (LCS) program, through comparison with a retrospective interpretation from a central laboratory., Materials and Methods: Consecutive baseline LDCTs (n = 3353) from a nationwide LCS program were investigated. In the institutional reading, 20 radiologists in 14 institutions interpreted LDCTs using computer-aided detection and semi-automated segmentation systems for lung nodules. In the retrospective central review, a single radiologist re-interpreted all LDCTs using the same system, recording any non-calcified nodules ≥ 3 mm without arbitrary rejection of semi-automated segmentation to minimize the intervention of radiologist's discretion. Positive results (requiring additional follow-up LDCTs or diagnostic procedures) were initially classified by the lung CT screening reporting and data system (Lung-RADS) during the interpretation, while the classifications based on the volumetric criteria from the Dutch-Belgian lung cancer screening trial (NELSON) were retrospectively applied. Variabilities in positive rates were assessed with coefficients of variation (CVs)., Results: In the institutional reading, positive rates by the Lung-RADS ranged from 7.5 to 43.3%, and those by the NELSON ranged from 11.4 to 45.0% across radiologists. The central review exhibited higher positive rates by Lung-RADS (20.0% vs. 27.3%; p < .001) and the NELSON (23.1% vs. 37.0%; p < .001), and lower inter-institution variability (CV, 0.30 vs. 0.12, p = .003 by Lung-RADS; CV, 0.25 vs. 0.12, p = .014 by the NELSON) compared to the institutional reading., Conclusion: Considerable inter-institution variability in the interpretation of LCS results is caused by different usage of the computer-assisted system., Key Points: • Considerable variability existed in the interpretation of screening LDCT among radiologists partly from the different usage of the computerized system. • A retrospective reading of low-dose chest CTs in the central laboratory resulted in reduced variability but an increased positive rate.