Purpose: This study aimed at applying a mathematical framework for the prediction of high-grade gliomas (HGGs) cell invasion into normal tissues for guiding the clinical target delineation, and at investigating the possibility of using tumor infiltration maps for patient overall survival (OS) prediction. Material & methods: A model describing tumor infiltration into normal tissue was applied to 93 HGG cases. Tumor infiltration maps and corresponding isocontours with different cell densities were produced. ROC curves were used to seek correlations between the patient OS and the volume encompassed by a particular isocontour. Area-Under-the-Curve (AUC) values were used to determine the isocontour having the highest predictive ability. The optimal cut-off volume, having the highest sensitivity and specificity, for each isocontour was used to divide the patients in two groups for a Kaplan-Meier survival analysis. Results: The highest AUC value was obtained for the isocontour of cell densities 1000 cells/mm3 and 2000 cells/mm3, equal to 0.77 (p < 0.05). Correlation with the GTV yielded an AUC of 0.73 (p < 0.05). The Kaplan-Meier survival analysis using the 1000 cells/mm3 isocontour and the ROC optimal cut-off volume for patient group selection rendered a hazard ratio (HR) of 2.7 (p < 0.05), while the GTV rendered a HR = 1.6 (p < 0.05). Conclusion: The simulated tumor cell invasion is a stronger predictor of overall survival than the segmented GTV, indicating the importance of using mathematical models for cell invasion to assist in the definition of the target for HGG patients.