Abstract: Objective In the era of targeted therapy, the efficacy and optimal dose of whole-brain radiotherapy+ simultaneous integrated boost （WBRT+SIB） for non-small cell lung cancer（NSCLC） patients with multiple or large volume brain metastases are unknown. This study analyzed the efficacy, safety and optimal dose of WBRT+SIB for NSCLC patients with multiple or large volume brain metastases. Methods Retrospective analysis was performed on the efficacy of WBRT+SIB in 58 patients with NSCLC brain metastasis in the Radiotherapy Department of Guangdong Provincial People's Hospital. Results 58 patients received WBRT+SIB, 8 patients （14%） achieved complete response（CR）, 46 patients （79%） achieved partial response（PR）, and 4 patients （7%） achieved stable disease（SD）. The median intracranial overall survival（OS） was （21.6±2.5） months and post-radiotherapy OS （r-OS） was （18.4±2.4） months. There was no significant difference in post-radiotherapy intracranial progression-free survival（r-iPFS） and r-OS between mutant NSCLC with multiple brain metastases at time of diagnosis group, mutant NSCLC with multiple brain metastases after initial diagnosis and no mutant NSCLC with multiple brain metastases at time of diagnosis（9.0 vs. 10.4 vs. 13.9 months,P=0.166;13.7 vs. 20.9 vs. 16.9 months,P=0.762）. The efficacy of intracranial-PFS（iPFS） and OS in no mutant NSCLC with multiple brain metastases at time of diagnosis and mutant NSCLC with multiple brain metastases after initial diagnosis, but worse than that in mutant NSCLC with multiple brain metastases at time of diagnosis group （12.5 vs. 14.7 vs. 25.7 months,P=0.047;17.6 vs. 22.5 vs. 30.6 months,P=0.048）. Grade 1 acute toxicity（CTC V4.0） is reported in 54 cases, grade 2 in 3 cases, grade 3 in 1 case, no grade 4 case. Grade 1 late toxicity （RTOG） is reported in 55 cases, grade 2 in 3 cases, no grade 3 and grade 4 cases. Conclusion WBRT+SIB is effective in NSCLC patients with multiple or large volume brain metastases, with tolerable toxic and side effects.