Background: Brain metastasis is the common place of tumor recurrence after resistance to crizotinib. The therapeutic modes on brain metastasis of ALK-positive NSCLC require multidisciplinary approach, including target therapy, chemotherapy and radiotherapy. Until to nowadays, there isn`t optimal therapeutic recommendations for these patients. Radiotherapy is the vital treatment for brain metastasis.Case presentation: We reported one ALK-positive NSCLC patient with brain metastasis after crizotinib. ALK rearrangement wasn`t found in blood sample of the patient by NGS. According to NCCN guideline, we gave the patient whole brain radiotherapy. It was unexpected that the number of brain metastasis increased after whole brain radiotherapy. After that, the patient was empirically used alectinib after radiotherapy failure. It achieved unexpected success in our patient. Conclusions: We got some enlightenment form the patient. Firstly, liquid biopsy is complementary to tissue biopsy in NSCLC, mainly in EGFR mutation. However, ALK detection should use tissue biopsy as much as possible. Secondly, we suggest the brain metastasis patient of NSCLC use the second generation TKI, such as alectinib, ceritinib, after resistance to crizotinib whether ALKr is positive or negative in liquid biopsy. Lastly, we believe that combined radiotherapy with TKIs is an optimal mode in the BM patient of NSCLC after resistance to crizotinib.