This study investigated the effects of co-administration of diphenyl diselenide [(PhSe)(2)] and 17β-estradiol (E(2)) on spatial reference, recognition, and working memories in ovariectomized (OVX) female mice. Sixty-day-old female adult Swiss mice were submitted to ovariectomy. From the 30th until 32nd day after ovariectomy, different doses of (PhSe)(2) (0.5-10mg/kg p.o.) were administrated to OVX mice 30min before each training of Morris Water Maze (MWM) test in order to find the highest subeffective dose for this drug. After that, OVX mice were divided into four groups: Oil, (PhSe)(2), E(2), and (PhSe)(2)+E(2). (PhSe)(2) (0.5mg/kg) and E(2) (0.1mg/kg) were administered to OVX mice from 30th to 32nd day after surgery, 30min before the training phases of behavioral tests (Open Field, MWM, Object Recognition, and T-maze). Our results demonstrated that 0.5mg/kg (PhSe)(2) plus 0.1mg/kg E(2) combined treatment improved spatial memory in the MWM test. By contrast, this same co-administration therapy was not effective in ameliorating neither delayed spontaneous alternation in the T-maze test nor object recognition memory deficits in OVX mice, although the dose of 0.5mg/kg (PhSe)(2) enhanced per se the object recognition memory in OVX mice. In conclusion, the current behavioral data suggest that a combination of (PhSe)(2) plus E(2) treatment seems to be a promising alternative to treat the cognitive decline related to menopause. Further studies should be conducted in order to determine an effective dose for (PhSe)(2) plus E(2) therapy on Object Recognition and T-maze tests.