Deuterium-depleted water (DDW) is a water which has a 6-7-fold less concentration of the naturally occurring deuterium (20-25ppm vs. 150ppm). While administrated for a longer period, it may reduce the concentration of deuterium throughout the body, thus activating cellular mechanisms which are depending on protons (channels, pumps, enzyme proteins). The aim of the present work was to study, for the first time in our knowledge, the possible influence of deuterium-depleted water (DDW) chronic administration in normal Wistar rats, as compared to a control group which received distilled water, on spatial working memory and the locomotor activity (as studied through Y-maze) or both short-term and long-term spatial memory (assed in radial 8 arms-maze task). Our results presented here showed no significant modifications in terms of spatial working memory (assessed through spontaneous alternation percentage) and locomotor activity (expressed through the number of arm entries) in Y-maze, as a result of DDW ingestion. Also, no significant differences between the DDW and control group were found in terms of the number of working memory errors in the eight-arm radial maze, as a parameter of short-term memory. Still, we observed a significant decrease for the number of reference memory errors in the DDW rats. In this way, we could speculate that the administration of DDW may generate an improvement of the reference memory, as an index of long-term memory. Thus, we can reach the conclusion that the change between the deuterium/hydrogen balance may have important consequences for the mechanisms that govern long-term memory, as showed here especially in the behavioral parameters from the eight-arm radial maze task.