OBJECTIVE: : To determine whether treatment with memantine plus vitamin D is more effective than memantine or vitamin D alone in improving cognition among patients with Alzheimer disease (AD). METHODS: : We studied 43 white outpatients (mean 84.7+/-6.3 years; 65.1% women) with a new diagnosis of AD, who had not taken anti-dementia drugs or vitamin D supplements. We prescribed memantine alone (n=18), vitamin D alone (n=17), or memantine plus vitamin D (n=8) for an average of 6 months. We assessed cognitive change with the Mini-Mental State Examination (MMSE). We used age, sex, pre-treatment MMSE score, and duration of treatment as covariables. RESULTS: : Before treatment, the 3 groups had comparable MMSE scores. At 6 months, participants taking memantine plus vitamin D increased their MMSE score by 4.0+/-3.7 points (P=0.034), while participants taking memantine alone remained stable (change of 0.0+/-1.8 points; P=0.891), as did those taking vitamin D alone (-0.6+/-3.1 points; P=0.504). Treatment with memantine plus vitamin D was associated with improvement in the MMSE score compared to memantine or vitamin D alone after adjustment for covariables (P<0.01). Mixed regression analysis showed that the visit by combined treatments (memantine plus vitamin D) interaction was significant (P=0.001), while memantine or vitamin D alone showed no effect. CONCLUSIONS: : Patients with AD who took memantine plus vitamin D for 6 months had a statistically and clinically relevant gain in cognition, underlining possible synergistic and potentiating benefits of the combination.