Background: Intertumor heterogeneity had been observed in various kinds of malignant tumors including non-small cell lung cancer. Comparing with extra-pulmonary metastasis, patients with multiple pulmonary nodules have a significantly higher rate of heterogeneity. The aim of this study was to compare the known driver mutations distribution among non-small cell lung cancer(NSCLC) patients with multiple intrapulmonary ground-glass nodules(GGNs). Methods: 35 consecutively resected lung cancer patients with multiple lung GGNs at a single institution (Tongji University, Shanghai, China) were analyzed for mutations in EGFR, KRAS, HER2, BRAF and PIK3CA together with genes fusion in ALK, ROS1 and RET. Results: The median age was 60 years old, male/female:12/23, never smoker/smoker: 25/10, PS 0/1: 22/13. Totally, 72 lesions were included into this analysis, including 9 of adenocarcinoma in situ, 9 minimal invasive adenocarcinoma and 54 invasive adenocarcinoma. Among them, 33 (45.8 %) tumors harbored EGFR mutations, including 13 were deletions in exon 19, 18 were L858R missense changes, and two were 19 deletion together with L858R mutations. 5 (6.9 %) harbored EML4-ALK fusions, 4 (5.6%)had HER2 mutations, 3(4.2%)had KRAS mutations, 1 had ROS1 fusion and BRAF mutation respectively. A majority of the mutations were mutually exclusive, except 1 both with EGFR mutation and ALK fusion. The discordant frequency rate of the driver mutation distribution was 68.6%(24/35) in the whole population, while it was 80%(24/30) in the patients harbored at least one of the detected driver mutations. In one of the 2 cases who had 3 resected lung lesions, exon21 L858R point mutation, exon 19 deletion, and L858R point mutation together with ALK fusion were found in the 3 tumor samples separately. Conclusions: The high incidence of inconsistent driver mutations distribution between multiple intrapulmonary nodules in this study suggested that these GGNs might arise as independent events and contributed to the higher rate of heterogeneity in intrapulmonary nodules. Patients with multiple GGNs should be given a separate staging and treatment strategy.