Purpose To compare the Vancouver risk calculator (VRC) with American College of Radiology (ACR) Lung Imaging Reporting and Data System (Lung-RADS) in predicting the risk of malignancy in the National Lung Screening Trial (NLST). Materials and Methods A total of 2813 patients with 4408 nodules (4078 solid, 330 subsolid) were available from the NLST for evaluation. Nodules were scored by using VRC with nine parameters (output was the percentage likelihood of malignancy; VRC threshold for malignancy likelihood set as greater than 5%) and Lung-RADS (output was category 2-4B; malignancy defined as category 4A or 4B; malignancy likelihood greater than 5%). Lung-RADS and VRC were compared for sensitivity, specificity, and accuracy for malignancy on a per-nodule and per-patient basis. Results Of 4408 total nodules, 100 of 4078 (2.5%) solid nodules were malignant and 10 of 330 (3%) subsolid nodules were malignant. On an overall per-nodule basis, the sensitivity, specificity, and accuracy for VRC and Lung-RADS were 93%, 90%, and 90% for VRC and 87%, 83%, and 83% for Lung-RADS, respectively (P = .077, P < .001, and P < .001, respectively). On a per-patient basis, the sensitivity, specificity, and accuracy for VRC and Lung-RADS were 93%, 85%, and 85% for VRC and 87%, 76%, and 76% for Lung-RADS, respectively (P = .077, P < .001, and P < .001, respectively). Conclusion The Vancouver risk calculator had superior overall accuracy than the Lung Imaging Reporting and Data System in predicting malignancy in the National Lung Screening Trial for total nodules, as well as on a per-patient basis. © RSNA, 2019 See also the editorial by Black in this issue.