The aim of this study was to compare computer-aided diagnosis (CAD) and visual reading for the detection of subsolid nodules (SSNs) in volumetrl measuremic low-dose computed tomography (LDCT) for lung cancer screening. Prospective visual detection (VD) and manuaent of SSN were performed in the 2303 baseline volumetric LDCTs of the Multicenter Italian Lung Detection trial. Baseline and 2- and 4-year LDCTs underwent retrospective CAD analysis, subsequently reviewed by 2 experienced thoracic radiologists. The reference standard was defined by the cumulative number of SSNs detected by any reading method between VD and CAD. The number of false-positive CAD marks per scan (FP/scan) was calculated. The positive predictive value of CAD was quantified per nodule (PPV) and per screenee (PPV). The sensitivity and negative predictive value were compared between CAD and VD. The longitudinal 3-time-point sensitivity of CAD was calculated in the subgroup of persistent SSNs seen by VD (ratio between the prevalent SSNs detected by CAD through 3 time points and the total number of persistent prevalent SSNs detected by VD) to test the sensitivity of iterated CAD analysis during a screening program. Semiautomatic characteristics (diameter, volume, and mass; both for whole nodule and solid component) were compared between SSN detected CAD-only or VD-only to investigate whether either reading method could suffer from specific sensitivity weakness related to SSN features. Semiautomatic and manual diameters were compared using Spearman ? correlation and Bland-Altman plot. Computer-aided diagnosis and VD detected a total of 194 SSNs in 6.7% (155/2,303) of screenees at baseline LDCT. The CAD showed mean FP/scan of 0.26 (604/2,303); PPV 22.5% (175/779) for any SSN, with 54.4% (37/68) for PSN and 19.4% for NSN (138/711; P < 0.001); PPV 25.6% (137/536). The sensitivity of CAD was superior to that of VD (88.4% and 34.2%, P < 0.001), as well as negative predictive value (99.2% and 95.5%, P < 0.001). The longitudinal 3-time-point sensitivity of CAD was 87.5% (42/48). There was no influence of semiautomatic characteristics on the performance of either reading method. The diameter of the solid component in PSN was larger by CAD compared with manual measurement. At baseline, CAD detected 3 of 4 SSNs, which were first overlooked by VD and subsequently evolved to lung cancer. Computer-aided diagnosis and VD as concurrent reading methods showed complementary performance, with CAD having a higher sensitivity, especially for PSN, but requiring visual confirmation to reduce false-positive calls. Computer-aided diagnosis and VD should be jointly used for LDCT reading to reduce false-negatives of either lone method. The semiautomatic measurement of solid core showed systematic shift toward a larger diameter, potentially resulting in an up-shift within Lung CT Screening Reporting and Data System classification.