PURPOSE This meta-analysis aims to combine and analyze randomized clinical trials comparing computed tomography lung screening (CTLS) versus either no screening (NS) or chest x-ray (CXR) in subjects with cigarette smoking history, to provide a precise and reliable estimation of the benefits and harms associated with CTLS. MATERIALS AND METHODS Data from all published randomized trials comparing CTLS versus either NS or CXR in a highly tobacco-exposed population were collected, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Subgroup analyses by comparator (NS or CXR) were performed. Pooled risk ratio (RR) and relative 95% CIs were calculated for dichotomous outcomes. The certainty of the evidence was assessed using the GRADE approach. RESULTS Nine eligible trials (88,497 patients) were included. Pooled analysis showed that CTLS is associated with: a significant reduction of lung cancer–related mortality (overall RR, 0.87; 95% CI, 0.78 to 0.98; NS RR, 0.80; 95% CI, 0.69 to 0.92); a significant increase of early-stage tumors diagnosis (overall RR, 2.84; 95% CI 1.76 to 4.58; NS RR, 3.33; 95% CI, 2.27 to 4.89; CXR RR, 1.52; 95% CI, 1.04 to 2.23); a significant decrease of late-stage tumors diagnosis (overall RR, 0.75; 95% CI, 0.68 to 0.83; NS RR, 0.67; 95% CI, 0.56 to 0.80); a significant increase of resectability rate (NS RR, 2.57; 95% CI, 1.76 to 3.74); a nonsignificant reduction of all-cause mortality (overall RR, 0.99; 95% CI, 0.94 to 1.05); and a significant increase of overdiagnosis rate (NS, 38%; 95% CI, 14 to 63). The analysis of lung cancer–related mortality by sex revealed nonsignificant differences between men and women ( P = .21; I-squared = 33.6%). CONCLUSION Despite there still being uncertainty about overdiagnosis estimate, this meta-analysis suggested that the CTLS benefits outweigh harms, in subjects with cigarette smoking history, ultimately supporting the systematic implementation of lung cancer screening worldwide.