The effect of 17beta-estradiol on the secondary damage following spinal cord injury (SCI) was examined in male rats subjected to moderate compression. Two doses of 17beta-estradiol (0.1 or 4 mg/kg) were injected i.p. immediately after spinal cord compression. Functional outcome was observed during 4 weeks following injury with two different tests. Release of cytokines (IL-1alpha, IL-1beta and IL-6) was assessed 6 h, 3 days and 1 week post-injury. Reactive astrocytes expressing the glial fibrillary acidic protein GFAP and vimentin, and diffusion of CD68-positive inflammatory cells were examined from 3 days to 4 weeks following SCI. Treatment with 17beta-estradiol significantly increased locomotor function from the first week until 4 weeks post-SCI. The injured spinal cord of 17beta-estradiol-treated rats expressed more IL-1alpha, IL-1beta and IL-6 than controls 6 h after injury. Moreover, 17beta-estradiol-treated rats showed reactive astrocytes as soon as 3 days following SCI, with increased GFAP expression, smaller lesion areas and more limited diffusion of CD68-positive cells after 1 week post-injury compared to controls. The number of CD68-positive cells was also reduced in 17beta-estradiol-treated rats one week post-SCI. However, these differences between 17beta-estradiol-treated and control rats disappeared after 4 weeks. These results suggest that 17beta-estradiol protects the spinal cord by stimulating early cytokines release and astroglial responses. These stimulations may prevent the area of damage from expanding and inflammatory cells to spread in the surrounding tissue during the critical first week following SCI. Although transient, these effects improved the locomotor recovery that was sustained over 4 weeks after injury.