Background: There is no consensus on whether patients with synchronous multiple lung cancers (SMLC) who present with lymph node metastasis (LNM) but whose epidermal growth factor receptor (EGFR) mutations are different are considered to have intrapulmonary metastases or multiple primary lung cancers. Few studies on these patients have been reported. Methods: The electronic medical records of patients with surgically resected multiple lung cancers between February 2016 and July 2019 were retrospectively reviewed, focusing on the clinical characteristics and prognosis of patients with LNM and different EGFR mutations. Results: A total of 125 patients were diagnosed with SMLC, and only 8 patients had LNM and different EGFR mutations. Their mean age was 61.43 +/- 8.08 years (range 47-69 years). EGFR detection suggested that 4 patients had completely different mutation types, and 4 patients had mutations in only 1 tumor. Only 1 of the 17 total lesions was squamous cell carcinoma, the rest were adenocarcinoma. All patients underwent adjuvant therapy after surgery. Except for 1 patient who underwent chemotherapy, the rest received tyrosine kinase inhibitor-targeted therapy. As at 15 October 2020, the average follow-up time was 28.68 +/- 10.74 months (range 10.5-40.5 months), and all patients were alive except 1 who died from extensive pleural metastasis. Conclusion: The current study highlights the clinical importance of EGFR detection in SMLC, especially in patients with LNM. SMLC with LNM and different EGFR mutations should be considered multiple primary lung cancers rather than intrapulmonary metastases, and comprehensive treatment based on surgery may be preferable in these patients due to a good prognosis.