Objective To evaluate the efficacy and safety of memantine in the treatment of Alzheimer’s disease (AD). Methods The randomized controlled trials (RCTs) about memantine vs. donepezil for patients with AD from January 1989 to July 2011 were searched in CBM, CNKI, WanFang Data, MEDLINE, OVID, EMbase and The Cochrane Library. Two reviewers independently screened the literatures, extracted the data, and evaluated the methodological quality. Then meta-analyses were conducted by using RevMan 5.0 software. Results The total 12 RCTs were included. Among the 2 716 patients involved, 1 459 were in the memantine group, while the other 1 302 were in the donepezil group. The results of meta-analyses showed that the efficacy of the memantine group was superior to that of the donepezil group in MMSE (MD=0.53, 95%CI 0.21 to 0.85, P=0.001), CIBIC-Plus (MD= –0.19, 95%CI –0.31 to –0.07, P=0.002), NPI (MD= –2.9, 95%CI –4.57 to –1.22, P=0.000 7) and SIB (MD=3.12, 95%CI 0.57 to 5.67, P=0.02), with significant differences; but the efficacy of the two groups was similar in ADCS-ADL19 (MD=0.29, 95%CI –0.03 to 0.60, P=0.07). There was no significant difference between the two groups in incidence of side effects (RR=1.14, 95%CI 0.94 to 1.38, P=0.17), but the tolerability of the memantine group was much better (RR=0.78, 95%CI 0.63 to 0.97, P=0.03). Conclusion Based on the current studies, memantine is superior to donepezil in treating Alzheimer’s disease (AD) at present. Although the side effects are similar to donepezil, memantine has much better intolerability and is considered to be safe and effective. For the quality restrictions and possible publication bias of the included studies, more double blind RCTs with high quality are required to further assess the effects.