Increasing evidence from behavioral and neuroimaging studies suggests that mesial temporal lobe epilepsy (mTLE) is possibly associated with the default-mode brain function. However, the alteration of coherent neural activities in such a default-mode network (DMN) in mTLE has yet to be investigated. The present study analyzed the resting-state functional MRI data from two groups of mTLE patients with left and right hippocampal sclerosis using independent component analysis. In comparison with healthy controls, decreased functional connectivity in the dorsal mesial prefrontal cortex, mesial temporal lobe and inferior temporal cortex was observed in these two patient groups. Moreover, the right but not left mTLE patients showed bilaterally decreased functional connectivity in the mesial temporal lobe and increased functional connectivity in the posterior cingulate cortex. The decreased functional connectivity of the mesial temporal lobe was related to the epilepsy duration, suggesting that the posterior cingulate cortex may play a compensatory role for the altered DMN in the right mTLE. These findings indicate that the DMN is widely affected even if a single network node is impaired. An extensive regional overlap between the DMN and the previously described epileptic network suggests that the widespread functional impairments in mTLE may attribute to an aberrant DMN. The distinct patterns of the DMN between the left and right mTLE support a view that there are different pathological mechanisms underlying these two types of epilepsies.