Objective Limited studies have shown an association between the methyl-CpG-binding protein2 ( MeCp2) genetic polymorphisms and systemic lupus erythematosus (SLE) in different populations, but the results are inconclusive. In order to get a precise and systematic estimation, a meta-analysis was performed. Methods A systematic literature search using English and Chinese databases (PubMed/Medline, Web of Knowledge, Wanfang Data (Chinese), etc.) for the eligible studies was performed. Based on heterogeneity among studies, random- or fixed-effects models were selected to analyze the risk of SLE associated with single-nucleotide polymorphisms (SNPs) of MeCP2 genetic polymorphisms. Results A significant increased risk of both SNPs of MeCP2 genetic variances associated with SLE was found. Analysis using a fixed-effects model found an increased risk of SLE with the A allele of rs2075596 (OR = 1.41, 95% CI: 1.34 to 1.49, p < 0.001), and the random-effects model also identified a risk factor of A allele of rs2239464 (OR = 1.31, 95% CI: 1.15 to 1.49, p = 0.001). Subgroup analysis and sensitivity analysis suggested that the major source of between-study heterogeneity stemmed from the difference between diverse ethnic groups. After omitting the smallest study, no publication bias was found, which further confirmed the reliability and stability of the meta-analysis. Conclusions Mutations of SNPs ( rs2075596, rs2239464) of MeCP2 showed increased risk of developing SLE. Large-scale multicenter epidemiological studies in selected populations with other risk factors are urgently required.