BackgroundThe sensitivity and specificity of minimal residual disease detected by circulating tumor DNA profiling (ctDNA MRD) in lung cancer, with particular attention to the distinction between landmark strategy and surveillance strategy, for predicting relapse in lung cancer patients after definitive therapy has yet to be determined.MethodsThe prognostic value of ctDNA MRD by landmark strategy and surveillance strategy was evaluated in a large cohort of patients with lung cancer who received definitive therapy using a systemic literature review and meta-analysis. Recurrence status stratified by ctDNA MRD result (positive or negative) was extracted as the clinical endpoint. We calculated the area under the summary receiver operating characteristic curves, and pooled sensitivities and specificities. Subgroup analyses were conducted based on histological type and stage of lung cancer, types of definitive therapy, and ctDNA MRD detection methods (detection technology and strategy such as tumor-informed or tumor-agnostic).ResultsThis systematic review and meta-analysis of 16 unique studies includes 1251 patients with lung cancer treated with definitive therapy. The specificity of ctDNA MRD in predicting recurrence is high (0.86–0.95) with moderate sensitivity (0.41–0.76), whether shortly after treatment or during the surveillance. The landmark strategy appears to be more specific but less sensitive than the surveillance strategy.ConclusionsOur study suggests that ctDNA MRD is a relatively promising biomarker for relapse prediction among lung cancer patients after definitive therapy, with a high specificity but suboptimal sensitivity, whether in landmark strategy or surveillance strategy. Although surveillance ctDNA MRD analysis decreases specificity compared with the landmark strategy, the decrease is minimal compared to the increase in sensitivity for relapse prediction of lung cancer.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12916-023-02849-z.