BACKGROUND: Although the association of multiple pulmonary metastases, and particularly miliary metastases, with response to gefitinib treatment in patients with nonsmall cell lung cancer has been reported, the association of miliary pulmonary metastases with epidermal growth factor receptor gene (EGFR) mutations remains unclear. METHODS: The authors retrospectively investigated the association of diffuse, random pulmonary metastases in patients with lung adenocarcinoma. The study included 163 Japanese patients who had unresectable, advanced lung adenocarcinoma diagnosed between April 2003 and March 2010. Computed tomography scans that were obtained at the time of diagnosis were analyzed by 2 investigators. For the purposes of this study, diffuse, random pulmonary metastases were defined as multiple nodules (n = 50; <= 3 cm in greatest dimension) distributed diffusely and randomly throughout the lungs. RESULTS: Of 163 patients, 55 had pulmonary metastases, and EGFR mutations were detected in 22 of those 55 patients. The mutations were identified preferentially among women (P = .15) and were identified significantly among patients who had a smoking history of <10 pack-years (P = .0057). Diffuse, random pulmonary metastases were identified in 11 of 22 patients who had EGFR mutations and in 4 of 33 patients who had the wildtype EGFR (P = .0043). On the basis of multivariate analyses, EGFR mutations were associated independently with a smoking history of <10 pack-years (P = .026) and with diffuse, random pulmonary metastases (P = .012). CONCLUSIONS: When patients with lung adenocarcinomas who had EGFR mutations developed pulmonary metastases, they tended to be diffuse and random, including military metastases. However, such metastases were much less common in patients who had lung adenocarcinomas with wild-type EGFR. Cancer 2011;117:819-25. (C) 2070 American Cancer Society