Background: Subcallosal cingulate (SCC) activity is associated with treatment response in major depressive disorder (MDD). Using electroconvulsive therapy (ECT) as a treatment model in this exploratory study, we addressed whether pretreatment SCC structural connectivity with corticolimbic-striatal circuitry relates to therapeutic outcome and whether these connectivity patterns change with treatment. Methods: Diffusion magnetic resonance imaging scans were acquired in 43 patients with MDD (mean [SD] age = 41  years; men/women: 18/25) before and within 1 week of completing an ECT index series and in 31 healthy control subjects scanned twice (mean [SD] age = 38  years; men/women: 17/18). Probabilistic tractography from subject-specific anatomically defined SCC seed regions to the ventral striatum (VS), anterior cingulate cortex (ACC), and bilateral medial prefrontal cortex (mPFC) was used to estimate structural connectivity in the target network. Results: SCC-mPFC connectivity was lower in responders (>50% symptom improvement) than nonresponders both before (p < .014) (difference 37%–96% left and right hemispheres) and after (p = .023) (difference 100% right hemisphere) treatment. SCC-mPFC connectivity in responders was also decreased compared with control subjects both at baseline (p = .012) and after ECT (p = .006), whereas nonresponders had SCC–right mPFC connectivity similar to that of control subjects. Subjects with MDD also showed decreased SCC-ACC connectivity compared with control subjects (baseline: p < .003, after ECT: p = .001), although SCC-ACC connectivity did not distinguish responders from nonresponders. Bilateral SCC-VS connectivity decreased (11%) with ECT (p = .021) regardless of treatment response. Conclusions: While SCC-ACC connectivity may be a hallmark of MDD compared with control subjects, lower pretreatment SCC-mPFC connectivity in ECT responders (compared with nonresponders and control subjects) suggests that connectivity in this pathway may serve as a potential biomarker of therapeutic outcome and be relevant for treatment selection.