Hexachlorobenzene's (HCB's) estrogenicity change and potential mechanisms when mixing with a typical natural estrogen, 17-Estradiol (E2), were investigated. Human breast cancer cell MCF-7 increase examination was used. The results showed that HCB had very strong estrogenicity, but the mixture of HCB and E2 showed strong rivalry effect, i.e., E2 and HCB greatly weakened each other on endocrine disrupting effect. Mechanism analyses showed that E2 and HCB could interfere with the endocrine system via the endocrine receptor channel and the MAPK signal channel. The rivalry effect between E2 and HCB was unrelated with the traditional endocrine receptor channel, but depended strongly on the non-traditional ERK channel. E2 decreased the HCB activation of ERK protein, and decreased the expression of p-ERK protein, thus interrupting the transcription of MAPK signal. The transcription factor analyses showed that E2 weakened the function of HCB mainly by decreasing the expression of c-Myc protein.