The present study revealed that (1) 5-aza-dC-induced demethylation can significantly increase the sensitivity of ovarian cancer cells to cisplatin as well as hMSH2 expression, (2) knockdown of hMSH2 expression could desensitize A2780 ovarian cancer cells to cisplatin, (3) the hMSH2 upstream region was significantly hypermethylated in the EOC tissue of platinum-resistant patients, and (4) the lower expression of hMSH2 due to hypermethylation of the upstream region was associated with the clinical outcome of patients with EOC. The gene discussed is MSH2; the disease is ovarian carcinoma.