Background: Combined use of memantine and acetylcholinesterase inhibitors (AChEIs) has shown improved outcomes in patients with Alzheimer's disease (AD). However, it is not clear which AChEI is the optimal for the combined treatment with memantine. Methods: A total of 110 AD patients were randomized to receive memantine and one of the following add-on drugs: placebo, donepezil, rivastigmine, galantamine, and huperzine A for 24 weeks (n=22). At baseline, 12 weeks, and 24 weeks, the patients were evaluated using mini-mental state examination (MMSE) and Alzheimer Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scales. Adverse events were recorded to analyze the safety profile. Results: The MMSE scores were significantly increased and the ADL scores were significantly decreased at 12 weeks and 24 weeks in all five groups compared with baseline (all P<0.01). At 24 weeks, patients treated with memantine+huperzine A showed better MMSE and ADL scores than those treated with memantine+placebo. Conclusions: Huperzine A may be an optimal choice for the combined therapy with memantine in treating AD.