This study was designed to evaluate the effects of a novel phytoestrogen, α-zearalanol (α-ZAL), and estradiol benzoate (B-E₂), on c-myc, c-fos, and EGFR expression in normal human breast tissues implanted into nude mice. A xenograft-model, pieces of normal human breast tissue implanted subcutaneously into 9-10-week-old athymic nude mice, was established. The mice were divided into five groups subjected to the following treatments: normal saline (Controls); α-ZAL at 1 and 5 mg/kg; and estradiol benzoate (B-E₂) at 1 and 5 mg/kg. Treatment was given every other day, and human breast tissues were removed for experiments after treatment for 30 days. The expression of c-myc, c-fos, and EGFR mRNAs were determined by in situ hybridization. α-ZAL decreased expression of c-myc (p < 0.05). About 1 mg/kg α-ZAL increased EGFR expression (p < 0.05) and two dosage of α-ZAL increased c-fos expression (p < 0.01) compared with control. B-E₂ significantly increased expression of c-myc, c-fos, and EGFR mRNAs expression compared with controls (p < 0.01). The extents of the increases in EGFRmRNA expression induced by α-ZAL and in c-fos mRNA by 5 mg/kg α-ZAL were lower than those induced by B-E₂ (p < 0.01). These data suggest that the phytoestrogen α-ZAL may be safer than estrogen on breast.