BACKGROUND: The combined use of chemotherapy (CT) and radiotherapy (RT) is becoming increasingly common in the treatment of surgically resected low-grade gliomas. However, whether RT or CT is associated with improved overall survival (OS) for low-grade gliomas without surgical resection is less clear. METHODS: The U.S. National Cancer Data Base was used to identify patients with histologically confirmed World Health Organization (WHO) grade 2 gliomas who received either RT alone or CT alone but did not undergo surgical resection from 2004 to 2013. OS was evaluated with Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and propensity score-matched analysis. RESULTS: In total, 1126 patients with WHO grade 2 gliomas were included, among whom 715 (63.5%) received RT alone and 411 (36.5%) CT alone. CT alone was associated with significantly longer OS when compared to RT alone on multivariable analysis and propensity-score matched analysis. Age less than 60 years and time from diagnosis to start of adjuvant therapy (RT or CT) greater than 30 days were also associated with longer OS. In subgroup analysis based on age, the survival advantage of CT alone over RT alone persisted in both age subgroups (< 60 years and >60 years). In subgroup analyses based on histology of glioma, CT alone was associated with longer OS in the astrocytoma and oligodendroglioma group, but not in the oligoastrocytoma group. CONCLUSIONS: Our results suggest that CT alone was independently associated with longer OS when compared with RT alone in patients with low-grade glioma but without surgical resection. This survival advantage persisted in both age subgroups, but it varied by histology of glioma.