The objective of this prospective study was to determine whether specific neuroanatomical sites were associated with increased risk of aspiration in acute stroke patients. Videofluoroscopic swallow studies (VSS) and computed tomography or magnetic resonance imaging scans were completed on consecutive male stroke patients (n = 54). Videofluoroscopic swallow studies were scored on a scale from 0 (normal swallowing) to 4 (severe dysphagia). Patients with scores of 0-1 were grouped together as having no risk of aspiration, and patients with scores of 2-4 were grouped together as having a risk of aspiration. Lesion analyses revealed that location appeared to be more critical than hemisphere or lesion size in predicting patients at risk of aspiration. Anterior locations and subcortical periventricular white matter sites were commonly lesioned in patients with risk of aspiration, whereas patients without risk of aspiration were more likely to have posterior lesions and lesions to subcortical gray matter structures. These data demonstrate that swallowing appears to be mediated by a distributed neural network that involves both cerebral hemispheres with descending input to the medulla; however, specific lesion locations may put patients at a greater risk of aspiration.