PURPOSE To investigate whether a panel of circulating protein biomarkers would improve risk assessment for lung cancer screening in combination with a risk model on the basis of participant characteristics. METHODS A blinded validation study was performed using prostate lung colorectal ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the performance of a four-marker protein panel (4MP) consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in combination with a lung cancer risk prediction model (PLCO_m2012) compared with current US Preventive Services Task Force (USPSTF) screening criteria. The 4MP was assayed in 1,299 sera collected preceding lung cancer diagnosis and 8,709 noncase sera. RESULTS The 4MP alone yielded an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.77 to 0.82) for case sera collected within 1-year preceding diagnosis and 0.74 (95% CI, 0.72 to 0.76) among the entire specimen set. The combined 4MP + PLCO_m2012 model yielded an area under the receiver operating characteristic curve of 0.85 (95% CI, 0.82 to 0.88) for case sera collected within 1 year preceding diagnosis. The benefit of the 4MP in the combined model resulted from improvement in sensitivity at high specificity. Compared with the USPSTF2021 criteria, the combined 4MP + PLCO_m2012 model exhibited statistically significant improvements in sensitivity and specificity. Among PLCO participants with ≥ 10 smoking pack-years, the 4MP + PLCO_m2012 model would have identified for annual screening 9.2% more lung cancer cases and would have reduced referral by 13.7% among noncases compared with USPSTF2021 criteria. CONCLUSION A blood-based biomarker panel in combination with PLCO_m2012 significantly improves lung cancer risk assessment for lung cancer screening.