Background This study investigated whether maintenance temozolomide (TMZ) after definitive therapy for locally advanced non-small-cell lung cancer (NSCLC) could decrease the incidence of brain metastasis (BM). Patients and Methods Eligible patients included those with stage IIIA, IIIB, or IV (for stage IV, only with malignant pleural/pericardial effusion) NSCLC with no BM at diagnosis and stable disease, partial response, or complete response after first-line chemotherapy using at least 2 agents. Patients were randomized to observation or TMZ (75 mg/m2 for 21 consecutive days followed by a 7-day rest for up to 6 cycles or progression). The primary end point was incidence of radiographically diagnosed BM within 12 months from day 1 of first-line chemotherapy. Secondary end points included overall survival (OS), time to progression, incidence of BM at first progression, and toxicity. Results The study was closed early on the basis of a futility analysis; 45 of 53 enrolled patients were evaluable from an original target of 100. No difference was noted in the incidence of BM at 1 year in the TMZ and observation groups (18% and 13%, respectively), in median time to progression (11.7 and 10.7 months, respectively), or in median OS (27.1 and 22.5 months, respectively). Common Terminology Criteria for Adverse Events grade 3 or 4 adverse events were 46% in the TMZ group and 19% in the observation group. Conclusions TMZ monotherapy does not appear to decrease the incidence of BM in patients with locally advanced NSCLC. These results considered in the context of the existing literature have implications for future clinical trial design.