Transient global amnesia (TGA) is an episodic dysfunction of declarative memory that usually resolves within 12 hours and whose underlying pathophysiological mechanisms are still unclear. Recent studies, on the basis of transient focal high-signal abnormalities in the hippocampus on diffusion-weighted imaging (DWI), suggest involvement of memory circuits in the temporo-mesial region. Out of a total of 65 patients presenting with acute or subacute TGA between May 2004 and May 2008, we retrospectively analysed 21 in whom a DWI sequence was performed. Five patients showed a focal hippocampal signal alteration both on DWI and on conventional T2; this alteration was no longer detectable on follow-up MRI two months later. The presence of transient DWI and T2 alterations in the hippocampal formation suggests that TGA could have a multifactorial, non-vascular aetiology. The presence of local susceptibility to neuronal metabolic stress emerges as a likely hypothesis.