Neuroimaging research has highlighted maladaptive thalamo-cortico-striatal interactions in obsessive-compulsive disorder as well as a more general deficit in prefrontal functioning linked with compromised executive functioning. More specifically, dysfunction in the ventromedial prefrontal cortex, a central hub in coordinating flexible behaviour, is thought to be central to obsessive-compulsive disorder symptomatology. We sought to determine the intrinsic alterations of the ventromedial prefrontal cortex in obsessive-compulsive disorder employing resting-state functional connectivity magnetic resonance imaging analyses with a ventromedial prefrontal cortex seed region of interest. A total of 38 obsessive-compulsive disorder patients and 33 matched controls were included in our analyses. We found widespread ventromedial prefrontal cortex hyperconnectivity during rest in patients with obsessive-compulsive disorder, displaying increased connectivity with its own surrounding region in addition to hyperconnectivity with several areas along the thalamo-cortico-striatal loop: thalamus, caudate and frontal gyrus. Obsessive-compulsive disorder patients also exhibited increased functional connectivity from the ventromedial prefrontal cortex to temporal and occipital lobes, cerebellum and the motor cortex, reflecting ventromedial prefrontal cortex hyperconnectivity in large-scale brain networks. Furthermore, hyperconnectivity of the ventromedial prefrontal cortex and caudate correlated with obsessive-compulsive disorder symptomatology. Additionally, we used three key thalamo-cortico-striatal regions that were hyperconnected with our ventromedial prefrontal cortex seed as supplementary seed regions, revealing hypoconnectivity along the orbito- and lateral prefrontal cortex-striatal pathway. Taken together, these results confirm a central role of a hyperconnected ventromedial prefrontal cortex in obsessive-compulsive disorder, with a special role for maladaptive crosstalk with the caudate, and indications for hypoconnectivity along the lateral and orbito pathways.