The present study assessed whether the mediodorsal nucleus (MD) of the primate thalamus subserves some of the same learning and memory functions mediated by its prefrontal cortical projection areas. Behavioral effects of MD lesions were evaluated in 14 young adult rhesus monkeys, using tests known to be sensitive to damage in different regions of the prefrontal cortex. Performance on a spatial delayed alternation task was significantly (P less than 0.01) impaired by MD lesions, and this impairment was significantly correlated (rs = 0.52) with damage to the posterior half of the mediodorsal nucleus. Such damage was also correlated significantly (rs = 0.51) with performance on another spatial memory task, delayed response; monkeys that sustained the largest lesions of the posterior mediodorsal nucleus were significantly (P less than 0.05) impaired on this task relative to operated animals suffering the least posterior MD damage. In contrast to their performance on spatial memory tasks, operated animals were not impaired on tests of object reversal or visual pattern discrimination. These results indicate that lesions of the mediodorsal nucleus can elicit a specific syndrome of spatial memory loss qualitatively similar to that observed after damage to the dorsolateral prefrontal cortex.