The aetiology, pathomechanisms and anatomical correlates of transient global amnesia (TGA) still remain obscure. Recently, focal MR-signal diffusion-weighted imaging (DWI) changes in the hippocampus have been described in patients with TGA, but the exact localization, long term outcome and pathophysiological nature of these lesions still remain unknown. The topography and time course of hippocampal DWI lesions in 41 TGA patients was studied using serial 3 T high-resolution MR-imaging and correlated to clinical and neuropsychometric results. Of these, 29 patients showed 36 DWI lesions with corresponding T2 lesions in the hippocampus within a time window of 48 h after onset. Almost all lesions (94%; 34/36) were selectively found in the CA-1 sector (Sommer sector) of the hippocampal cornu ammonis. Most DWI lesions (8/10) were already detectable in the peri-acute phase <6 h after onset of symptoms. A follow-up study 4–6 months after the episode did not show evidence for residual structural sequelae of these lesions (n = 20/20). A venous MR angiography of the intracranial dural sinus showed an asymmetric venous drainage in 21/24 (88%) patients. In 11/16 (69%) patients with unilateral lesions, the asymmetry corresponded to the side of the DWI lesion. Significant episodic verbal memory deficits in the acute phase (n = 14/18) were associated with lesions of the dominant hemisphere while impairment of visuospatial memory was associated with lesions of the non-dominant hemisphere. Persistent neuropsychological sequelae were not detected 4–6 months after the episode (n = 16). This is the first prospective study combining high-resolution imaging and neuropsychometry analysing the detailed functional anatomy and outcome of hippocampal DWI/T2 lesions in TGA supporting the view the TGA being a benign transient disorder. The TGA can be considered a model for a focal transient perturbation of memory circuits in the temporo-mesial region.