Coronary artery calcium (CAC) is a known risk factor for cardiovascular (CV) events and mortality but is not yet routinely evaluated in low-dose computed tomography (LDCT)-based lung cancer screening (LCS). The present analysis explored the capacity of a fully automated CAC scoring to predict 12-year mortality in the Multicentric Italian Lung Detection (MILD) LCS trial. The study included 2239 volunteers of the MILD trial who underwent a baseline LDCT from September 2005 to January 2011, with a median follow-up of 190 months. The CAC score was measured by a commercially available fully automated artificial intelligence (AI) software and stratified into five strata: 0, 1–10, 11–100, 101–400, and > 400. Twelve-year all-cause mortality was 8.5% (191/2239) overall, 3.2% with CAC = 0, 4.9% with CAC = 1–10, 8.0% with CAC = 11–100, 11.5% with CAC = 101–400, and 17% with CAC > 400. In Cox proportional hazards regression analysis, CAC > 400 was associated with a higher 12-year all-cause mortality both in a univariate model (hazard ratio, HR, 5.75 [95% confidence interval, CI, 2.08–15.92] compared to CAC = 0) and after adjustment for baseline confounders (HR, 3.80 [95%CI, 1.35–10.74] compared to CAC = 0). All-cause mortality significantly increased with increasing CAC (7% in CAC ≤ 400 vs. 17% in CAC > 400, Log-Rank p-value <0.001). Non-cancer at 12 years mortality was 3% (67/2239) overall, 0.8% with CAC = 0, 1.0% with CAC = 1–10, 2.9% with CAC = 11–100, 3.6% with CAC = 101–400, and 8.2% with CAC > 400 (Grey’s test p < 0.001). In Fine and Gray’s competing risk model, CAC > 400 predicted 12-year non-cancer mortality in a univariate model (sub-distribution hazard ratio, SHR, 10.62 [95% confidence interval, CI, 1.43–78.98] compared to CAC = 0), but the association was no longer significant after adjustment for baseline confounders. In conclusion, fully automated CAC scoring was effective in predicting all-cause mortality at 12 years in a LCS setting.