Background: Osimertinib has been shown to be effective against epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC), but so far all clinical trials have targeted performance status (PS) 0 to 1 cases. The efficacy and safety of osimertinib in EGFR T790M-positive NSCLC patients with poor PS remain elusive. Methods: We conducted an open-label, multi-center, single-arm phase II study to evaluate the efficacy and safety of osimertinib in patients with EGFR T790M mutation-positive NSCLC who had Eastern Cooperative Oncology Group PS scores of 2 to 4. Patients received 80 mg of osimertinib once daily. The primary endpoint was progression-free survival (PFS). The planned sample size was 18 patients to achieve power of at least 80% with one-sided alpha of 0.05 and expected and threshold PFS as 8.2 months and 3.0 months. Results: Eighteen patients (4 men and 14 women) were enrolled between June 2017 and November 2018. The median age was 77 years (range: 55–85 years). Ten, six, and two patients had PS scores of 2, 3, and 4, respectively. All patients had adenocarcinoma with common EGFR mutations and were previously treated with first- or second-generation EGFR- tyrosine kinase inhibitors, and 10 patients (56%) had central nervous system (CNS) metastasis. The overall median PFS was 7.0 months (90% confidence interval: 5.5-8.9 months). The overall response rate (ORR) was 53%, the median time to first response was 1.5 months, the median duration of response was 6.7 months, and the median overall survival (OS) was 12.7 months. Moreover, improved PS scores were observed in 13 patients (72%) including six with PS 2, six with PS 3, and one with PS 4. Osimertinib also showed an ORR of 60% in the patients with CNS metastasis, and the median PFS and OS were 6.5 months and 22.0 months, respectively. Although anemia, rash, and anorexia were frequently reported, the incidence of grade 3 adverse events was low, and no grade 4 or 5 events were observed. Interstitial lung disease (ILD) was observed in three patients (two with grade 2, one with grade 1). All three patients discontinued osimertinib treatment and recovered from ILD. Conclusions: Osimertinib therapy could be a promising treatment option for patients with EGFR T790M mutation-positive advanced NSCLC who have poor PS. Clinical trial information: UMIN000027655.