Objective: To investigate the association between estradiol therapy and incidence of breast cancer, taking into consideration of different types of combined progestogen, the duration of exposure and the type of regimen.Method: A systematic review and meta-analysis.Result: A total of 14 studies were included in our study. In estradiol-only therapy analysis, meta-analysis resulted a pooled OR=0.90, 95% CI (0.40, 2.02) from the RCTs and pooled OR=1.11, 95% CI (0.98, 1.27) from observational studies. However, in the analysis of estradiol-progestogen therapy, the risk of breast cancer varies according to the type of progestogen and the duration with more than five years (OR=2.43, 95% CI (1.79, 3.29)) presented a higher risk than using less than five years (OR = 1.49, 95% CI (1.03, 2.15)).Conclusions: Estradiol-only therapy carries no risk for breast cancer, while the breast cancer risk varies according to the type of progestogen. Estradiol therapy combined with medroxyprogesterone, norethisterone and levonorgestrel related to an increased risk of breast cancer, estradiol therapy combined with dydrogesterone and progesterone carries no risk. The breast cancer risk rise progressively by prolonged use, furthermore, comparing to sequential therapy, continuous therapy carries a higher risk.