Radiotherapy is used to treat one out of two cancer patients, and it leverages ionizing radiation to damage the tumor tissue, possibly sparing the surrounding healthy tissue1. The treatment is scheduled based on the tumor features aiming at maximizing the probability of controlling the tumor while minimizing the probability of radiation toxicity, i.e. side effects. In this scenario, hypoxia within the tumor negatively impacts radiotherapy efficacy. Therefore, we investigated how microvascular morphology affects oxygen distribution, determining hypoxic regions and treatment failure. To this aim, we developed a mixed-dimensional computational model to describe the oxygen delivery in the microenvironment, considering the microvasculature as a one-dimensional structure embedded in a 3D environment2–4. Based on the fluid flow description, we modeled the oxygen delivery accounting for diffusive and convective phenomena in the tissue, the vascular network, and the exchange between them. The radiotherapy treatment is the simulated describing a schedule compatible with the current clinical practice. We used the gold standard approach, the linear-quadratic model, to estimate the fraction of cells surviving the treatment and its success probability. The model is modified as reported in the literature to account for the oxygen effect on the treatment efficacy, leading to a 3D description of the surviving fraction, which is a peculiarity of this work. This test was repeated considering different oxygenation scenarios and radiation sources (photons, protons, carbon ions). Results show the correlations between the hypoxic volume fractions (with pO2 lower than 1 mmHg) and the success probability for the treatment. Additionally, we found that these hypoxic regions might be present locally, even in highly vascularized tissue, if the network is not uniformly distributed, as it might happen in cancer. It is still to be investigated whether these areas are visible clinically via imaging, possibly helping identify sub-voxel hypoxia. Finally, carbon ions seem more effective than photons and protons in the presence of hypoxia, as expected from the literature. These results help us understand how the microvascular network morphology affects tumor oxygenation and the radiotherapy outcome.