Gliomas are primary brain tumors associated with a poor prognosis partly due to resistance to conventional therapies. To overcome this problem, we investigated the combined effects of gamma knife radiosurgery (GKS) and an antiangiogenic agent, thalidomide (THD), or a chemotherapeutic agent, temozolomide (TMZ), on a rat glioma model. GKS (20 Gy single dose) alone and/or drugs (for 3 days) were delivered 14 or 18 days after stereotactic implantation of C6/LacZ glioma cells into the brains of Sprague-Dawley rats. A group of animals treated with or without drugs for 3 days was irradiated on day 18 and sacrificed at 24 h after GKS to evaluate cell proliferation, apoptosis and microvessel density. The other group of animals was irradiated on day 14 and sacrificed at day 5 after GKS for the measurement of tumor volume. Apoptosis of endothelial cells in the tumor beds was only observed in the early period after GKS. Decreased cell proliferation and increased tumor cell apoptosis were observed in rat gliomas treated with GKS and THD or TMZ. The combination treatments with GKS and THD or GKS and TMZ also decreased microvessel density, i.e. angiogenesis, more effectively compared with GKS treatment alone. The combination of GKS and THD was the most effective regimen, resulting in a significant decrease of tumor volume. We suggest that the antitumor effect of GKS on glioma is enhanced by the addition of THD. Therefore, combined therapy with GKS and THD might be a favorable treatment for gliomas.