Simple SummaryGlioblastomas are the most common primary malignant brain tumors, with a devastating survival perspective. The treatment concept of interstitial photodynamic therapy (iPDT) enables the light-induced destruction of tumor cells based on the combination of a photosensitizer that selectively accumulates in the tumor and light to activate the photosensitizer. The tumor region is illuminated by minimally invasively inserted optical fibers. Under this approach, prolonged overall survival was observed. An analysis of the patient characteristics and the evolution of the MRI data before treatment and during follow-up was performed to identify potential predictors of an improved survival outcome. It was found that the methylation status of the DNA-repair enzyme MGMT is an important factor regarding survival. Other commonly assessed parameters, such as the tumor volume, necrosis–tumor ratio, and contrast enhancement after therapy, did not seem to significantly affect survival. Overall, the iPDT-treated patients showed very promising results regarding a sustained absence of their tumors and prolonged overall survival.AbstractBackground: The treatment of glioblastomas, the most common primary malignant brain tumors, with a devastating survival perspective, remains a major challenge in medicine. Among the recently explored therapeutic approaches, 5-aminolevulinic acid (5-ALA)-mediated interstitial photodynamic therapy (iPDT) has shown promising results. Methods: A total of 16 patients suffering from de novo glioblastomas and undergoing iPDT as their primary treatment were retrospectively analyzed regarding survival and the characteristic tissue regions discernible in the MRI data before treatment and during follow-up. These regions were segmented at different stages and were analyzed, especially regarding their relation to survival. Results: In comparison to the reference cohorts treated with other therapies, the iPDT cohort showed a significantly prolonged progression-free survival (PFS) and overall survival (OS). A total of 10 of 16 patients experienced prolonged OS (≥ 24 months). The dominant prognosis-affecting factor was the MGMT promoter methylation status (methylated: median PFS of 35.7 months and median OS of 43.9 months) (unmethylated: median PFS of 8.3 months and median OS of 15.0 months) (combined: median PFS of 16.4 months and median OS of 28.0 months). Several parameters with a known prognostic relevance to survival after standard treatment were not found to be relevant to this iPDT cohort, such as the necrosis–tumor ratio, tumor volume, and posttreatment contrast enhancement. After iPDT, a characteristic structure (iPDT remnant) appeared in the MRI data in the former tumor area. Conclusions: In this study, iPDT showed its potential as a treatment option for glioblastomas, with a large fraction of patients having prolonged OS. Parameters of prognostic relevance could be derived from the patient characteristics and MRI data, but they may partially need to be interpreted differently compared to the standard of care.