BACKGROUND: Alectinib has been established as a standard of care for patients with treatment-naive anaplastic lymphoma kinase-rearranged (ALK-positive) advanced non-small-cell lung cancer (NSCLC); however, it has rarely been compared with the sequential approach (crizotinib followed by alectinib) in China. This study aimed to compare real-world alectinib upfront data with either real-world sequential approach data or clinical trial first-line alectinib data. METHODS: The patients who received alectinib in the real-world setting were monitored from August 2016 to November 2020. The patients' characteristics were well balanced using the inverse probability of treatment weighting (IPTW) method. Real-world progression-free survival (rwPFS), real-world overall survival (rwOS), and real-world intracranial progression-free survival (rwiPFS) were calculated. To compare the effectiveness of alectinib in real-world setting with that in the ALEX study, data from the ALEX study were analyzed. RESULTS: This study included 311 patients who were divided into three groups: alectinib group (n=102), sequential group (n=63), and alectinib group in ALEX (n=146). The rwPFS and rwOS were similar between the alectinib and sequential groups. However, alectinib group was associated with a lower risk of central nervous system progression than sequential group. Compared with alectinib group in ALEX, the alectinib group in the real world had a significantly longer PFS [hazard ratio (HR), 0.57; 95% confidence interval (CI): 0.37-0.89; P=0.01] and OS (HR, 0.42; 95% CI: 0.21-0.82; P=0.01) after IPTW. CONCLUSIONS: Our real world data suggested that sequential group was associated with a higher risk of progression in the brain than the alectinib upfront treatment. However, both treatments had similar survival in advanced ALK-positive NSCLC. Patients with advanced ALK-positive NSCLC in the real-world setting had significantly improved outcomes than those in the ALEX study.