Abstract Background Hippocampal avoidance during prophylactic cranial irradiation (HA-PCI) is proposed to reduce neurocognitive decline, while preserving the benefits of PCI. We evaluated whether (HA-)PCI induces changes in white matter (WM) microstructure and whether sparing the hippocampus has an impact on preserving brain network topology. In addition, we evaluated associations between topological metrics with hippocampal volume and neuropsychological outcomes. Methods In this multicenter randomized phase 3 trial (NCT01780675), small-cell lung cancer (SCLC) patients underwent neuropsychological testing and diffusion tensor imaging (DTI) before, 4 months (33 PCI, 37 HA-PCI) and 1 year (19 PCI, 17 HA-PCI) after (HA-)PCI. Changes in WM microstructure were investigated using whole-brain voxel-based analysis of fractional anisotropy (FA) and mean diffusivity (MD). Both hippocampal and whole-brain graph measures were used to evaluate the topological organization of structural networks. Correlation analysis was performed to associate topological metrics with neuropsychological outcomes and hippocampal volume. Results Both HA-PCI and PCI were associated with decreased FA in major WM tracts, such as the corpus callosum, at 4 months and 1 year post-treatment. While these FA decreases did not differ significantly between treatment groups, only PCI demonstrated increased MD over time. In addition, PCI showed decreased global efficiency and increased characteristic path length over time when compared with HA-PCI. Significant correlations were found between whole-brain graph measures and neuropsychological outcomes. Conclusion While both techniques induce important changes in the WM microstructure, HA-PCI might better preserve the topological organization of brain networks than PCI. The neuroprotective role of hippocampal sparing still needs further investigation.