Background: Mutational status of the IDH1/2 gene and co-deletion of on chromosome 1p/19q (co-del 1p/19q) is gaining further relevance for the evaluation of clinical outcome in lower grade glioma. Out of the established clinical and imaging parameters known to influence survival in these tumors, contrast enhancement (CE) has been reported to indicate poor outcome in the past. The present study aimed at re-assessing the value of clinical and imaging parameters in lower grade glioma within the framework of molecular markers using a machine learning approach (random survival forests, RSF) as well as conventional Cox regression modeling. Methods: 301 patients with grade II (n = 181) or grade III diffuse glioma (n = 120) were stratified according to their molecular profile (presence of IDH1/2 mutation and/or co-deletion 1p/19q.) Preoperative magnetic resonance (MR) imaging was reviewed and volumetrical analyses of CE and T₂ volumes were performed. Multivariate cox models and RSF were trained on this data set using five-fold cross validation to assess the predictive value of pre-therapeutic molecular and imaging factors as well as age, Karnofsky performance status, surgical procedure and adjuvant therapy to predict the individual risk for each patient. As a measure of prediction accuracy, the concordance indices for Cox and RSF models were determined. Results: RSF modeling revealed presence of IDH1/2 mutation, co-deletion 1p/19q and WHO II to be the most relevant factors for favorable outcome in lower grade glioma. In IDH1/2 mutant tumors, both conventional Cox regression modeling and RSF analyses show that CE on initial MR imaging is a prognostic factor for survival independently of its magnitude in both co-deleted and non-co-deleted tumors (p < 0.05). In contrast, presence of CE on initial MRI is not associated with outcome in IDH1/2 wildtype tumors. Likewise, the RSF model identified predictive influence of CE in the IDH1/2 mutant tumors only. Conclusions: In patients with diffuse IDH1/2 wildtype gliomas WHO grade II/III, CE is not associated with survival. In tumors with an IDH1/2 mutation, presence of CE on initial MRI is linked to inferior survival.