Background Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, and close associations between AD and diabetes have been found. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, as newly-developed oral hypoglycaemic agents, were evaluated as a possible therapy for AD. Aim We systematically evaluated the efficacy and safety of PPAR-gamma agonists in the treatment of AD and amnestic mild cognitive impairment (aMCI), the prodromal stage of AD. Methods A search of the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure (until July 2014) was conducted, and included randomized controlled trials. Dichotomous data were expressed as risk ratios (RRs) with 95 % confidence intervals (CIs), and continuous data were expressed as mean differences (MD) with 95 % CIs. The results were pooled using a random-effects model. Results Nine eligible studies were identified, with 4,327 participants. Using the Alzheimer's Disease Assessment Scale-Cognitive subscale, pioglitazone was found to be efficacious, especially for patients with comorbid diabetes (MD -3.47, 95 % CI -4.40 to -2.54). Rosiglitazone was not efficacious, even for apolipoprotein E (APOE) epsilon 4 non-carriers (MD -0.31, 95 % CI -1.12 to 0.51). There was no increase in any adverse events (AEs) or serious AEs compared with placebo. Peripheral edema was the most frequent AE related to PPAR-gamma agonist treatment (RR 4.14, 95 % CI 2.37-7.23). Conclusions There is insufficient evidence to support the use of rosiglitazone in aMCI and AD patients in order to improve cognitive performance. Nonetheless, the efficacy of pioglitazone seems to be promising, particularly for patients with comorbid diabetes, however this needs to be further confirmed by well-designed trials with large sample sizes. PPAR-gamma agonists such as rosiglitazone and pioglitazone are generally well-tolerated in AD and aMCI patients.