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Background: It has been indicated that there is a relationship between vitamin B12 status and cognitive functioning. Measurement of serum vitamin B12 is routinely performed in patients with memory loss during initial diagnosis. Noticing the role of cholinergic system and vitamin B12 on memory, the aim of this experimental study was to examine the effect of the interactions between vitamin B12 and nicotine on memory retention in passive avoidance learning in adult male rats. Materials and Methods: The present study was an experimental one. Drugs, including vitamin B12 (0.01, 0.02, 0.03, 0.05, 0.1, and 1 µg/rat) and nicotine (0.1, 0.5, and 1 µg/rat) were administrated after training session intracerebroventriculary (i.c.v.). The drugs were used (i.c.v.) in a volume of 1µl/rat immediately after the training session. The level of memory retention was evaluated by passive avoidance learning. Twenty-four hours after training, a retention test was performed to determine long-term memory. Statistical analysis was carried out using one-way ANOVA test. Results: The results showed that the administration of vitamin B12 and nicotine significantly increased memory retention in rats. Nicotine significantly increased the response to vitamin B12 in memory retention process. Conclusion: Vitamin B12 through interaction with cholinergic system acts in memory retention process.