Introduction: Retinoid signaling has been argued to have favorable effects on Alzheimer's disease (AD). We studied the role of chronic intracerebroventricular (ICV) injection of all-trans retinoic acid (ATRA) on the amyloid-beta (A beta) model of AD. Methods: Adult male rats weighing 260-330 g were divided into 12 groups of 8 each. Six groups of rats received ATRA (3nM, 30nM, 3 mu M, 0.3mM, 30mM/rat; ICV) or DMSO 1% (2 mu l/rat; ICV), bilaterally and in a chronic manner (6 times, twice a week). Forty eight hours following the last injection, memory performance was assessed using a passive avoidance paradigm. One group received A beta (10 mu g/rat; ICV), bilaterally. The control group received DMSO 1% (2 mu l/rat; ICV). Twenty days later memory performance was assessed. Three groups of rats received A beta (10 mu g/rat; ICV) and then ATRA (3nM or 30nM/rat; ICV) or DMSO 1%, chronically (6 times, twice a week). Another group received DMSO 1% (2 mu l/rat; ICV) and then, DMSO 1%, chronically (6 times, twice a week). Results: ATRA at doses 0.3mM and 30mM/rat impaired memory retrieval by decreasing step-through latency (STL) and increasing time spent in the dark compartment (TDC), significantly. However, moderate doses (3nM and 30nM/rat) did not change memory performance. ATRA (30nM/rat) increased STL and decreased TDC and NST in the A beta-treated rats, significantly compared to the group received A beta-DMSO 1%. Conclusion: The results propose a potential prophylactic effect of ATRA in the ICV A beta model of AD and indicate the prominence of retinoic acid signaling as a target for AD prevention.