Objective: The aim of this study was to develop a radiomics signature for prediction of progression-free survival (PFS) in lower-grade gliomas and to investigate the genetic background behind the radiomics signature. Methods: In this retrospective study, training (n = 216) and validation (n = 84) cohorts were collected from the Chinese Glioma Genome Atlas and the Cancer Genome Atlas, respectively. For each patient, a total of 431 radiomics features were extracted from preoperative T2-weighted magnetic resonance images. A radiomics signature was generated in the training cohort, and its prognostic value was evaluated in both the training and validation cohorts. The genetic characteristics of the group with high-risk scores were identified by radio-genomic analysis, and a nomogram was established for prediction of PFS. Results: There was a significant association between the radiomics signature (including 9 screened radiomics features) and PFS, which was independent of other clinicopathologic factors in both the training (P < 0.001, multivariable Cox regression) and validation (P = 0.045, multivariable Cox regression) cohorts. Radiogenomic analysis revealed that the radiomics signature was associated with the immune response, programmed cell death, cell proliferation, and vasculature development. A nomogram established using the radiomics signature and clinicopathologic risk factors demonstrated high accuracy and good calibration for prediction of PFS in both the training (C-index, 0.684) and validation (C-index, 0.823) cohorts. Conclusions: PFS can be predicted non-invasively in patients with LGGs by a group of radiomics features that could reflect the biological processes of these tumors.