Abstract Purpose: The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited. Experimental Design: Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score–weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays. Results: One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33–1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52–8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed. Conclusions: In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.