This prospective study was performed to determine the efficacy and safety of temozolomide (TMZ) plus thalidomide during and after radiation therapy (RT) in pediatric patients with newly diagnosed diffuse pontine glioma (DPG). Seventeen patients with pediatric DPG were enrolled between November 2004 and March 2008. The median age was eight years (range, 3-16 years); seven patients were male and ten were female. With the exception of one glioblastoma case, which was diagnosed via open biopsy, all diagnoses were established using neuroradiological studies. The authors used the Korean Society for Pediatric Neuro-Oncology (KSPNO)-A053 protocol. The mean follow-up period was 12 months (range, 8.5-25 months). Five patients were withdrawn from the study. The rates of response to treatment and survival were analyzed in 12 patients. Ten out of the 12 patients showed a partial response (PR), whereas one patient exhibited stable disease (SD) and another patient had progressive disease (PD). The tumor control rate was 92% (11/12) and the response rate was 83% (10/12). The median progression-free survival (PFS) of the 12 patients was 7.2 months (95% confidence interval (CI), 3.6-10.7). Six-month and twelve-month PFS were 58.3 and 16.7%, respectively. Overall survival (OS) was 12.7 months (95% CI, 10.4-15.1). One and two-year survival were 58.3 and 25%, respectively. The main adverse effect was hematological toxicity, with four patients exhibiting grade 3 or 4 toxicity. All patients tolerated the regimen well enough to continue the adjuvant chemotherapy. No Pneumocystis jiroveci pneumonia was noted. The TMZ plus thalidomide regimen was safe and tolerated well enough to be administered on an outpatient basis. Larger studies are required to demonstrate the efficacy of this regimen.