Although several studies have evaluated the efficacy of thiazolidinediones (TZD) for the treatment of Alzheimer’s disease (AD), investigation of the impact of apolipoprotein E (ApoE) gene polymorphisms on the efficacy of TZD remains insufficient. We investigated the impact by conducting a systematic review and meta-analysis. MEDLINE, Cochrane Library, and Japana Centra Revuo Medicina were searched to identify relevant studies based on eligibility criteria. Mean differences (MD) of Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score with 95% confidence intervals (CI) were calculated for subgroups stratified by ApoE genotype. To evaluate the impact of ApoE gene polymorphisms, meta-regression analysis was also conducted to calculate the regression coefficient (Coef) of ApoE expression status with 95% CI. Three randomized controlled studies comparing rosiglitazone and placebo, with a total of 2381 subjects met the eligibility criteria. ApoE expression status was reported in 983 individuals (ApoE4-positive, 141; ApoE4-negative, 842). When compared to placebo, rosiglitazone significantly decreased ADAS-Cog score in ApoE4-negative individuals (MD, −1.37; 95% CI, −2.09 to −0.65), but significantly increased ADAS-Cog score in ApoE4-positive individuals (MD, 2.18; 95% CI, 0.52 to 3.85). The meta-regression analysis showed a significant association between efficacy and ApoE expression status (Coef, 3.55; 95% CI, 1.42 to 5.68). Although the present results should be interpreted with caution because of the limited number of studies, our findings suggest that ApoE gene polymorphisms impact the efficacy of rosiglitazone for AD patients. This finding would provide useful information for the development of new agents for AD.