Background: Recent studies show that the use of circulating tumor DNA (ctDNA) has potential to guide precision medicine and transform the management of early-stage lung cancers. We aim to investigate whether plasma is suitable for detecting tumor‐derived DNA in patients with stage I single-lesion lung cancer and multifocal lung cancer which has rarely been investigated. Methods: Matched tumor tissues (n = 114) and plasma samples (n = 95) from Chinese patients with stage I lung cancer (n = 95), including 80 patients with single-lesion and 15 patients with multiple primary lung cancer (MPLC) diagnosed by American College of Chest Physicians (ACCP) guidelines, were analyzed by Acornmed panel with 808 cancer-related genes. Results: Using tumor tissue-based results as the gold standard, we performed variant-level assessment of the ctDNA tests. In patients with single-lesion, sequencing detected alterations in 98.8% (79/80) ctDNA and 9.3% (74/797) of variants in ctDNA were detected by corresponding tDNA. Among them, 31.3% (25/80) patients had at least one overlapping variant called by tDNA and ctDNA, and 5% (4/80) patients shared EGFR in both tDNA and ctDNA. Meanwhile, we identified 2 mutated EGFR in ctDNA that were not detected in tissues. As for multiple primary lung cancers, 86.7% (13/15) of MPLC patients had ≥1 alteration in ctDNA. In addition, 7.4% (9/122) of variants in ctDNA were detected by corresponding tDNA in MPLC. The overall concordance for all variants detected in both ctDNA and any tDNA of patients was 53.3% (8/15) in MPLC, with EGFR and KRAS as the most two frequent mutations. Furthermore, mutations consistent with ctDNA were detected in 29.4% (10/34) of the lesions in MPLC. Conclusions: Our analysis showed that plasma with high mutation detection rate and considerable concordance rate with tDNA maybe a powerful complement to tissues for molecular testing in lung cancer. Furthermore, ctDNA detection not only may be able to overcome the heterogeneity of tumors but also more comprehensively reflect the disease state of patients with multifocal lung cancer.