Lung nodules detected by chest computed tomography (CT) often require invasive biopsies for definitive diagnosis, leading to unnecessary procedures for benign lesions. A blood-based biomarker test that predicts lung cancer risk in CT-detected nodules could help stratify patients and direct invasive diagnostics toward high-risk individuals. In this multicenter, single-blinded clinical trial, we evaluated a test measuring plasma levels of p53, anti-p53 autoantibody, CYFRA 21-1, and anti-CYFRA 21-1 autoantibody in patients with CT-detected lung nodules. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, and subgroup analyses by gender, age, and smoking status were performed. A total of 1,132 patients who had CT-detected lung nodules, including 885 lung cancer cases and 247 benign lesions, were enrolled from two academic hospitals in South Korea. The test demonstrated a sensitivity of 78.4% (95% CI: 75.7-81.1) and specificity of 93.1% (95% CI: 90.0-96.3) in predicting lung cancer in CT-detected nodules. The PPV was 97.6%, and the NPV was 54.6%. Performance was consistent across gender (sensitivity 79.3% in men and 76.8% in women) and age groups, with a specificity of 93.4% in men and 92.7% in women. Stage I lung cancer was detected with a sensitivity of 80.6%. The lung cancer test based on 9G technology presented here offers a non-invasive method for stratifying lung cancer risk in patients with CT-detected nodules. Its integration into clinical practice could reduce unnecessary interventions and foster earlier detection.