Background: The mechanisms underlying the antidepressant effect and cognitive side effects of Electroconvulsive Therapy (ECT) remain elusive. The measurement of cerebral perfusion provides an insight into brain physiology. Objective: We investigated ECT-related perfusion changes in depressed patients and tested whether these changes correlate with clinical effects. Methods: A sample of 22 in-patients was examined at three time points: 1) within two days before, 2) within one week after, and 3) six months after an ECT series. Cerebral perfusion was quantified using arterial spin labeling magnetic resonance imaging. The primary regions of interest were the bilateral dorsolateral prefrontal cortices (DL-PFC) and hippocampi. The depression severity was assessed by the six-item Hamilton Depression Rating Scale, and cognitive performance by the Screen for Cognitive Impairment in Psychiatry. A linear mixed model and partial correlation were used for statistical analyses. Results: Following an ECT series, perfusion decreased in the right (−6.0%, p =.01) and left DL-PFC (−5.6%, p =.001). Perfusion increased in the left hippocampus (4.8%, p =.03), while on the right side the increase was insignificant (2.3%, p =.23). A larger perfusion reduction in the right DL-PFC correlated with a better antidepressant effect, and a larger perfusion increase in the right hippocampus with worse cognitive impairment. Conclusion: ECT-induced attenuation of prefrontal activity may be related to clinical improvement, whereas a hippocampal process triggered by the treatment is likely associated with cognitive side effects.