OBJECTIVES: Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative condition and is the most common cause of dementia. Several studies show it generates a high economic burden. The aim of this study was to conduct a systematic literature review to determine the safety and efficacy of rivastigmine patch alone or in combination with memantine compared with memantine monotherapy in the treatment of moderate to severe AD.  METHODS: A systematic search of the literature was conducted in Medline, Embase, Cochrane Database of Systematic Reviews, Lilacs, Cochrane Central Register of Randomized Controlled Trials, Cochrane Database of Abstracts of Reviews of Effects, Clinicaltrials.gov and WHO ICTRP platform. Included studies were randomized controlled trials of patients diagnosed with moderate to severe AD (diagnosed by standardized criterio), evaluating outcomes of effectiveness and safety.  RESULTS: Original search yielded 5022 references, 66 full-text articles were checked by two independent reviewers. Finally 14 studies (8 of them randomized clinical trials) were included for analysis (8 from the US, 2 from Germany, and 1 each from Italy, Japan, Korea and Thailand). The results of experimental studies comparing doses of rivastigmine patches indicate a possible difference in some of the outcomes of effectiveness such as performance in activities of daily living, instrumental activities, and overall functioning in patients with moderate and severe AD, without significant difference in safety outcomes. A trend in favor of combination therapy in some of the outcomes as change in Mini Mental State Examination score and instrumental daily activities was observed. CONCLUSIONS: The available evidence supports the use of rivastigmine, and the association with memantine seems an appropriate therapeutic option in selected cases.