Receptor-interacting protein 140 (RIP140) is a negative transcriptional coregulator of nuclear receptors such as estrogen, retinoic acid or glucocorticoid receptors. Recruitment of RIP140 results in an inhibition of target gene expression through different repressive domains interacting with histone deacetylases or C-terminal binding proteins. In this study, we analyzed the role of RIP140 activity in memory processes using RIP140-deficient transgenic mice. Although the RIP140 protein was clearly expressed in the brain (cortical and hippocampus areas), the morphological examination of RIP140(-/-) mouse brain failed to show grossly observable alterations. Using male 2-month-old RIP140(-/-) , RIP140(+/-) or RIP140(+/+) mice, we did not observe any significant differences in the open-field test, rotarod test and in terms of spontaneous alternation in the Y-maze. By contrast, RIP140(-/-) mice showed long-term memory deficits, with an absence of decrease in escape latencies when animals were tested using a fixed platform position procedure in the water maze and in the passive avoidance test. Noteworthy, RIP140(-/-) mice showed decreased swimming speed, suggesting swimming alterations that may in part account for the marked alterations measured in the water maze. Moreover, RIP140(+/-) and RIP140(-/-) mice showed a significant increase in immobility time in the forced swimming test as compared with wild-type animals. These observations showed that RIP140 gene depletion results in learning and memory deficits as well as stress response, bringing to light a major role for this transcriptional coregulator in the neurophysiological developmental mechanisms underlying cognitive functions.