GBM is the most common primary malignant neoplasm of the central nervous system in adults. Fotemustine (FTM) is a cytotoxic alkylating agent and a lipophilic chloroethylnitrosourea derivative. Its mechanism of action consists mainly in inducing DNA strand breaks and cross-linking. Genistein, one of the soy-derived isoflavones, exerts its anticancer properties via several mechanisms, including inhibition of tyrosine phosphorylation, weak estrogenic and anti-estrogenic properties, as an antioxidant, inhibition of topoisomerase II, inhibition of angiogenesis, and induction of cell differentiation in a number of human tumors. We aimed to investigate the anti-proliferative synergistic effect of genistein with fotemustine on human glioblastoma multiforme U87-MG cells. This study was also designed to answer the following question: Do the p53, EGFR, COX-2 genes' expression patterns differ in treatment of these both drugs alone and in combination?