Abstract Background In multiple primary lung adenocarcinomas (MPLAs), the relationship between imaging and gene mutations remains unclear. This retrospective study aimed to identify the correlation of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) status with CT characteristics in MPLA patients. Methods Sixty-seven patients (135 lesions) with MPLAs confirmed by pathology were selected from our institution. All subjects were tested for EGFR mutations and ALK status and underwent chest CT prior to any treatment. The criteria for MPLA definitions closely adhered to the comprehensive histologic assessment (CHA). Results Among MPLA patients, EGFR mutations were more common in females (p = 0.002), in those who had never smoked (p = 0.010), and in those with less lymph node metastasis (p < 0.001), and the tumours typically presented with ground-glass opacity (GGO) (p = 0.003), especially mixed GGO (p < 0.001), and with air bronchograms (p = 0.012). Logistics regression analysis showed that GGO (OR = 6.550, p = 0.010) was correlated with EGFR mutation, while air bronchograms were not correlated with EGFR mutation (OR = 3.527, p = 0.060). A receiver operating characteristic (ROC) curve yielded area under the curve (AUC) values of 0.647 and 0.712 for clinical-only or combined CT features, respectively, for prediction of EGFR mutations, and a significant difference was found between them (p = 0.0344). ALK-positive status was found most frequently in MPLA patients who were younger (p = 0.002) and had never smoked (p = 0.010). ALK positivity was associated with solid nodules or masses in MPLAs (p < 0.004) on CT scans. Logistics regression analysis showed that solid nodules (OR = 6.550, p = 0.010) were an independent factor predicting ALK positivity in MPLAs. For prediction of ALK positivity, the ROC curve yielded AUC values of 0.767 and 0.804 for clinical-only or combined CT features, respectively, but no significant difference was found between them (p = 0.2267). Conclusion Among MPLA patients, nonsmoking women with less lymph node metastasis and patients with lesions presenting GGO or mixed GGO and air bronchograms on CT were more likely to exhibit EGFR mutations. In nonsmoking patients, young patients with solid lesions on CT are recommended to undergo an ALK status test.