Osimertinib showed encouraging efficacy in patients with advanced EGFR T790M-positive NSCLC in previous randomized controlled trials. This real-world study aimed to evaluate the effectiveness and safety of osimertinib in a real-world setting. This observational study (NCT03133234) included 74 patients with metastatic EGFR T790M-positive NSCLC who progressed on prior EGFR TKI therapy and received osimertinib between May 2016 and April 2018 at the Kiang Wu Hospital in Macau. Response rate (RR) and other endpoints (progression-free survival [PFS], overall survival [OS], disease control rate [DCR], stable disease rate, and adverse events) were assessed. Survival data were estimated using the Kaplan-Meier method. All patients had stage IV lung adenocarcinoma and 25.6% had brain metastases; median age was 58 years (range 28-84 years) and 83.8% of patients had received at least three prior lines of treatment. The median duration of osimertinib treatment was 8 months (range, 1-25 months). RR and DCR were 67.5% (95% CI 56.9-78.1) and 79.8% (95% CI 70.7-88.9), respectively, while 12.1% had stable disease. The median PFS was 9.0 months (95% CI 6.7-11.2 months), and the median OS was 12.0 months (95% CI 8.8-15.1 months). Nausea (25.8%) and decreased appetite (20.2%) were the most common adverse events associated with osimertinib treatment. Even though most patients had at least three lines of prior treatment, real-world RR and PFS with osimertinib in this study were consistent with those from randomized controlled trials; no new safety signals were observed.