In order to identify epigenetic markers of β-thalassemia, a genome-wide profiling method named differential methylation hybridization was used to search these differentially methylated genes. Unsupervised hierarchical clustering and molecular annotation system were used to analyze the data, and methylation-specific PCR and real-time PCR were used to confirm the differentially methylated genes. This system was validated by detecting 13 cases, 10 of which were homo-zygous β-thalassaemia. Totally 113 genes were identified as methlyation-enriched genes (ratio ≥ 2.0, P < 0.05) and 96 genes were identified as hypomethylated genes in both groups (ratio ≤ 0.5, P < 0.05). The promoter of the gene of La ribonucleoprotein domain family (LARP2) was significantly hypermethylated in β-thalassemia, and the expression of LARP2 was significantly lower in β-thalassemia. Hypermethylation of the LARP2 promoter was correlated with its lower expression in β-thalassemia and our chip-based DNA methylation detection system can provide earlier diagnosis of β-thalassemia using this epigenetic marker.