Background: Electroconvulsive therapy (ECT) is an effective treatment for severe depression and is shown to increase hippocampal volume and modulate hippocampal functional connectivity. Whether variations in hippocampal structural connectivity occur with ECT and relate to clinical response is unknown. Methods: Patients with major depression (n = 36, 20 women, age 41.49 ± 13.57 years) underwent diffusion magnetic resonance imaging at baseline and after ECT. Control subjects (n = 32, 17 women, age 39.34 ± 12.27 years) underwent scanning twice. Functionally defined seeds in the left and right anterior hippocampus and probabilistic tractography were used to extract tract volume and diffusion metrics (fractional anisotropy and axial, radial, and mean diffusivity). Statistical analyses determined effects of ECT and time-by-response group interactions (>50% change in symptoms before and after ECT defined response). Differences between baseline measures across diagnostic groups and in association with treatment outcome were also examined. Results: Significant effects of ECT (all p < .01) and time-by-response group interactions (all p < .04) were observed for axial, radial, and mean diffusivity for right, but not left, hippocampal pathways. Follow-up analyses showed that ECT-related changes occurred in responders only (all p < .01) as well as in relation to change in mood examined continuously (all p < .004). Baseline measures did not relate to symptom change or differ between patients and control subjects. All measures remained stable across time in control subjects. No significant effects were observed for fractional anisotropy and volume. Conclusions: Structural connectivity of hippocampal neural circuits changed with ECT and distinguished treatment responders. The findings suggested neurotrophic, glial, or inflammatory response mechanisms affecting axonal integrity.