Diffuse brainstem glioma is a rare disease in adults. Radiotherapy (RT) is usually considered to be the standard treatment. However, the role of chemotherapy in treating relapses after RT is unclear, and this study aimed to assess the use of temozolomide (TMZ) in this situation. We conducted a retrospective analysis of patients from our database with "low grade" adult diffuse infiltrating brainstem glioma who received TMZ at relapse after failing RT. The patients were diagnosed by histology or MRI criteria compatible with a low-grade glioma. The tumors were localized in the pons, medulla oblongata or midbrain, excluding supratentorial or infratentorial tumors that had infiltrated the brainstem secondarily. The patients' clinical and radiological responses were assessed, and their progression free survival (PFS) and overall survival (OS) time were estimated. Fifteen adult patients (median age 34 years) fulfilled the inclusion criteria. Histological analysis was available in 5 cases and showed grade II oligodendroglioma (2 cases), grade II oligoastrocytoma (2 cases), and grade II astrocytoma (1 case). Ten patients were selected by MRI criteria only. All patients received RT as initial treatment and had a median PFS of 34.2 months (95 % CI 24.1-44.2). The median KPS at the time of relapse was 80. TMZ was administered orally at 150-200 mg/m(2) for 5 days, every 28 days. Clinical improvement after TMZ was observed in 9 cases (60 %), whereas radiological assessment detected responses in 6/15 cases, including 4 partial and 2 minor responses. The estimated median PFS after TMZ was 9.5 months (95 % CI 7.9-11), and the median OS was 14.4 months (95 % CI 10.5-18.2). Grade 3 thrombopenia was observed in 26 % of cases. TMZ could be useful after RT failure in adult patients with recurrent diffuse "low grade" brainstem glioma.