Brain metastases (BM) cause morbidity and mortality in patients with non-small cell lung cancer (NSCLC). The use of upfront epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and withholding of whole-brain radiation therapy (WBRT) is controversial. We aim to investigate the impact of WBRT on overall survival (OS). After screening 1384 patients, a total of 141 EGFR-mutated patients with NSCLC and BM were enrolled. All patients received EGFR-TKIs between 2011 and 2015. Ninety-four patients (66.7 %) were treated with WBRT (TKI + WBRT group). With a median follow-up of 20.3 months (95% confidence interval (CI), 16.9-23.7), the median OS after the diagnosis of BM was 14.3 months (95% CI, 9.5 to 18.3) in the TKI + WBRT group and 2.3 months (95% CI, 2 to 2.6) in the TKI alone group. On multivariate analysis, WBRT ( < 0.001), female, surgery to primary lung tumor, and surgery to BM were associated with improved OS. The 1-year OS rate was longer in the TKI+WBRT group than that in the TKI alone group (81.9% vs 59.6%, = 0.002). In conclusion, this is the first study to demonstrate the negative survival impact from the omission of WBRT in patients with EGFR-mutant NSCLC.