Temozolomide (TMZ) has been used as a first-line therapy against low-grade gliomas (LGGs) combined with other chemotherapy drugs. However, there has been no reliable index predicting TMZ response of patients with LGGs. In this study, we aim to investigate the relationship between gene expressions and the prognosis of TMZ therapy in LGGs. We integrated transcriptome and clinical data of 171 LGGs from the Chinese Glioma Genome Atlas (CGGA). Consensus LASSO Cox regression was used to identify 14 key genes related to different clinical outcomes under TMZ chemotherapy. We constructed and evaluated a risk score based on the 14 genes. Patients with LGGs of lower risk scores (low-risk group) generally had better survival than those LGGs of higher risk scores (high-risk group), which is independent of clinicopathological factors. High-risk patients showed activation of innate and humoral-type immunity. The prognostic contribution of the risk score was validated in an independent validation cohort of 65 patients. Besides, combined with three independent predictors (grade, IDH1 mutation status, and chr1p19q co-deletion status), we further developed a nomogram to predict the benefit from TMZ treatment in LGGs. Our results indicate that transcriptome-based index can optimize the treatment strategy for patients with LGGs under TMZ therapy.