Background: The aim of this prospective monocentric study was to assess the inter-observer agreement for tumor volume delineations by multiparametric MRI and 18-F-FET-PET/CT in newly diagnosed, untreated high-grade glioma (HGG) patients. Methods: Thirty patients HGG underwent O-(2-[18F]-fluoroethyl)-l-tyrosine(18F-FET) positron emission tomography (PET), and multiparametric MRI with computation of rCBV map and K2 map. Three nuclear physicians and three radiologists with different levels of experience delineated the 18-F-FET-PET/CT and 6 MRI sequences, respectively. Spatial similarity (Dice and Jaccard: DSC and JSC) and overlap (Overlap: OV) coefficients were calculated between the readers for each sequence. Results: DSC, JSC, and OV were high for 18F-FET PET/CT, T1-GD, and T2-FLAIR (>0.67). The Spearman correlation coefficient between readers was ≥0.6 for these sequences. Cross-comparison of similarity and overlap parameters showed significant differences for DSC and JSC between 18F-FET PET/CT and T2-FLAIR and for JSC between 18F-FET PET/CT and T1-GD with higher values for 18F-FET PET/CT. No significant difference was found between T1-GD and T2-FLAIR. rCBV, K2, b1000, and ADC showed correlation coefficients between readers <0.6. Conclusion: The interobserver agreements for tumor volume delineations were high for 18-F-FET-PET/CT, T1-GD, and T2-FLAIR. The DWI (b1000, ADC), rCBV, and K2-based sequences, as performed, did not seem sufficiently reproducible to be used in daily practice.