BACKGROUND: Safflower is one of those herbal medicines that many studies rely on its use for the treatment of menstrual problems and diseases of the circulatory system. The flowers of this plant have long been used as a sexual stimulant medication. Furthermore there is evidence about its effects on the infertility and sexual disorders. Objectives: Considering the effect of this plant on infertility, this study was designed to investigate the role of the aqueous extract of Safflower on the histomorphometric structure of female genital system in mice. Methods: 30 female balb/c mice were randomly divided into 3 equal groups. In group one, Safflower extract was given orally for 45 consecutive days at the dose of 40mg/kg. Safflower extract (80 mg/kg) was given orally to mice in group two for 45 days. Mice in group three (Control group) received water in the same volume, way and time. Results from present study were analyzed statistically using ANOVA and Tukey's test. Results: The results showed that long term use of Safflower extract increased ovarian weight of mice (group one: 0.8±0.04, group two: 1.1±0.07) compared to control group (0.4±0.06), significantly (p<0.05).  Histomorphological studies revealed that use of Safflower increased the number and diameter of secondary follicles (group one: 3±0.57; 9±0.66, group two: 3.25±0.25; 9.08±0.3), graafian follicles (group one: 1.1±0.17; 7.66±0.54, group two: 1.2±0.13; 8±0.75) and corpus luteum (group one: 4.75±0.75; 5.27±0.29, group two: 4.75±0.47; 5.4±0.31) significantly (p<0.05). However, the number of atretic follicles were decreased in experimental groups (group one: 2.5±0.0.28, group two: 2.25±0.62) significantly (p<0.05). Furthermore, the diameter of granulosa layer (group one: 4.58±0.3, group two: 3.25±0. 3) and colosum oophorus (group one: 2.5±0.18, group two: 2.58±0. 15) in experimental groups were changed compared to control group (4.66±0.33, 1.87±0.15,) significantly (p<0.05). Safflower had no significant effects on the histomorphological structure of uterus (p>0.05).  Conclusions: It can be concluded that the aqueous extract of Safflower is more effective on ovaries compared to uterus and may have positive effects on fertility in female mice.