The anatomical basis and cognitive profile of diencephalic amnesia remain unclear. We report a two-part study. First, we studied 4 patients with bilateral medial thalamic infarctions using magnetic resonance imaging and comprehensive neuropsychological testing. All patients were followed for more than 1 year. Using a stereotactic method, we plotted the lesions in an atlas delineating the probable structure involved. Secondly, in 2 monkeys, using autoradiography, we traced the pathway from the amygdala to the dorsomedial nucleus, paying particular attention to the intrathalamic course of the amygdalothalamic projections. Our findings were (1) patients develop amnesia when infarctions are located anteriorly; (2) in patients with amnesia, the lesions can be small and strategically located, probably interfering with both hippocampal-related neural structures such as the mamillothalamic tract, and amygdala-related neural structures such as the ventroamygdalofugal pathway; and (3) a specific component of the latter is situated lateral but immediately adjacent to the mamillothalamic tract in the monkey, enabling both structures to be damaged bilaterally by small mirror image lesions. The amnesia is characterized by deficits in anterograde verbal and visual learning and in retrograde amnesia, but motor learning is preserved. We raise the possibility that bilateral diencephalic lesions may interfere particularly with temporal aspects of memory.