Few studies have directly compared the clinical and anatomical characteristics of patients with progressive aphasia to those of patients with aphasia caused by stroke. In the current study we examined fluent forms of aphasia in these two groups, specifically semantic dementia (SD) and persisting Wernicke’s aphasia (WA) due to stroke. We compared 10 patients with SD to 10 age- and education-matched patients with WA in three language domains: language comprehension (single words and sentences), spontaneous speech and visual semantics. Neuroanatomical involvement was analyzed using disease-specific image analysis techniques: voxel-based morphometry (VBM) for patients with SD and overlays of lesion digitized lesion reconstructions in patients with WA. Patients with SD and WA were both impaired on tasks that involved visual semantics, but patients with SD were less impaired in spontaneous speech and sentence comprehension. The anatomical findings showed that different regions were most affected in the two disorders: the left anterior temporal lobe in SD and the left posterior middle temporal gyrus in chronic WA. This study highlights that the two syndromes classically associated with language comprehension deficits in aphasia due to stroke and neurodegenerative disease are clinically distinct, most likely due to distinct distributions of damage in the temporal lobe.