This phase II, open-label study evaluated the efficacy and safety of erlotinib as second-line therapy in non-small-cell lung cancer (NSCLC) patients with brain metastases (BM). Forty-eight patients aged 18–75 years with Eastern Cooperative Oncology Group performance status 0–2, confirmed adenocarcinoma or activating epidermal growth factor receptor (EGFR) mutation-positive NSCLC, and asymptomatic BM without extracranial progressive disease after first-line platinum-doublet chemotherapy were recruited. Treatment comprised erlotinib 150 mg/day. The primary end point was progression-free survival (PFS) determined by RECIST. The median PFS was 10.1 months 95% confidence interval (CI) 7.1–12.3 for intracranial progression and 9.7 months (95% CI 2.5–17.8) for intracranial and systemic progression. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease 15.2 months (95% CI 8.3–22.2) versus 4.4 months (95% CI 0.0–11.6); P = 0.02. The median overall survival was 18.9 months (95% CI 14.4–23.4); 6-month and 1-year survival rates were 85% and 73%, respectively. Overall response rate was 58.3%. Most common adverse events were rash (77.1%), paronychia (20.8%), hyperbilirubinemia (16.7%), and diarrhea (14.6%); these were predominantly of grade 1/2. Single-agent erlotinib was active and well tolerated in NSCLC patients with BM. Further studies are warranted.