Resting-state functional connectivity reflects correlations in the activity between brain areas, whereas effective connectivity between different brain areas measures directed influences of brain regions on each other. Using the latter approach, we compare effective connectivity results in patients with major depressive disorder (MDD) and control subjects.We used a new approach to the measurement of effective connectivity, in which each brain area has a simple dynamical model, and known anatomical connectivity is used to provide constraints. This helps the approach to measure the effective connectivity between the 94 brain areas parceled in the automated anatomical labeling (AAL2) atlas, using resting-state functional magnetic resonance imaging. Moreover, we show how the approach can be used to measure the differences in effective connectivity between different groups of individuals, using as an example effective connectivity in the healthy brain and in individuals with depression. The first brainwide resting-state effective-connectivity neuroimaging analysis of depression, with 350 healthy individuals and 336 patients with major depressive disorder, is described.Key findings are that the medial orbitofrontal cortex, implicated in reward and subjective pleasure, has reduced effective connectivity from temporal lobe input areas in depression; that the lateral orbitofrontal cortex, implicated in nonreward, has increased activity (variance) in depression, with decreased effective connectivity to and from cortical areas contralateral to language-related areas; and that the hippocampus, implicated in memory, has increased activity (variance) in depression and increased effective connectivity from the temporal pole.Measurements of effective connectivity made using the new method provide a new approach to causal mechanisms in the brain in depression.