Objective To investigate the modulatory effect of progesterone on peripheral pain. Methods Female SD rats were divided into four groups, namely, a vehicle group, a progesterone (500 μg) group, an RU38486 (20 μg) group and a progesterone (500 μg) plus RU38486 (20 μg) group. Von-Frey hair test was adopted to determine the peripheral mechanical pain thresholds at the following 3 time points: preinjection,30 min and 60 min after subcutaneous injection at the neck. Local effect of progesterone was also tested in SD rats by Von-Frey hair test 15 min after plantar injection of progesterone (25 μg)and normal saline (control). Results The peripheral mechanical pain threshold was significantly increased 30 min after subcutaneous injection of progesterone at the neck compared with the vehicle group, but the threshold was not significantly different 60 min after injection. RU38486 injection at the neck significantly decreased the pain threshold of plantar at 30 min and 60 min after injection,and the peripheral mechanical pain threshold was not significantly altered at 30 min and 60 min after co-injection of progesterone and RU38486.RU38486 could block the pain inhibiting effect of progesterone. The peripheral mechanical pain threshold was also increased 15 min after plantar injection of progesterone compared with the control group. Conclusion Our findings suggest that progesterone can inhibit the peripheral mechanical pain, which might be mediated by progesterone receptor.