Hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter in glioblastoma (GBM) is a predictive biomarker associated with improved treatment outcome. In clinical practice, MGMT methylation status is determined by biopsy or after surgical removal of the tumor. This study aims to investigate the feasibility of non-invasive medical imaging based “radio-genomic” surrogate markers of MGMT methylation status. The imaging dataset of the RSNA-ASNR-MICCAI Brain Tumor Segmentation (BraTS) challenge allows exploring radiomics strategies for MGMT prediction in a large and very heterogeneous dataset that represents a variety of real-world imaging conditions including different imaging protocols and devices. To characterize and optimize MGMT prediction strategies under these conditions, we examined different image preprocessing approaches and their effect on the average prediction performance of simple radiomics models. We found features derived from FLAIR images to be most informative for MGMT prediction, particularly if aggregated over the entire (enhancing and non-enhancing) tumor with or without inclusion of the edema. Our results also indicate that the imaging characteristics of the tumor region can distort MR-bias-field correction in a way that negatively affects the prediction performance of the derived models.