PURPOSE: The updated Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (lung-molGPA) index provide more accurate survival prediction for patients diagnose with advanced non-small cell lung cancer (NSCLC) with brain metastases (BM). Given that the value of cranial radiotherapy (CRT) is still controversial for NSCLC patients with BM, this retrospective study aimed to evaluate the value of CRT and optimal timing in NSCLC patients with initial BM after stratified with lung-molGPA index. METHODS: This study screened NSCLC patients with initial BM in our cancer center from February 2012 to July 2018. The prognosis value of CRT and optimal timing was evaluated with Kaplan-Meier survival analysis and the patients were classified into lung-molGPA0-2 and lung-molGPA2.5-4 group. Upfront CRT was defined as received CRT within 3 months after initial diagnosis and without BM progression, other CRT was classified into deferred CRT. RESULTS: Overall, 288 patients were enrolled in our study, 156 patients received CRT. The median follow-up time was 47 months. In the entire cohort, the median PFS and OS were 9.2 and 17.0 months, respectively. In the lung-molGPA2.5-4 group, CRT can bring significantly overall survival benefit for NSCLC patients with initial BM (HR: 0.48, 95% CI: 0.34-0.68, P < 0.0001), and the upfront CRT can further expand this survival benefits compared with deferred CRT (HR: 0.49, 95% CI: 0.27-0.89, P = 0.0026). But this phenomenon was not observed in lung-molGPA0-2 group patients. CONCLUSION: Upfront CRT could bring significantly overall survival benefit for these patients with lung-molGPA2.5-4 but not for patients with lung-molGPA0-2.