Previous studies have shown that both 17β-estradiol (E2) treatment and chronic stress may attenuate post-OVX weight gain in the female rat. However, the interaction between E2 and stress is unclear. This study examined the effect of E2 treatment and chronic immobilization stress on body weight. Adult OVX Sprague-Dawley rats were randomly assigned to one of four treatment groups in a 2X2 factorial design examining hormone treatment [vehicle (VEH) or E2, sc] and stress (no stress vs stress 60 min/day for 22 days). After 22 days, E2 significantly inhibited weight gain and food intake in OVX rats. In contrast, chronic stress reduced body weight only in control OVX animals but did not affect food intake. E2 reduced circulating leptin levels in non-stressed animals, but not in animals subjected to chronic immobilization. Western blot analysis indicated that E2 treatment increased leptin receptor (Ob-Rb) expression in the medial basal hypothalamus (MBH); however, this treatment also increased suppressor of cytokine signaling 3 (SOCS3), which is an inhibitor of leptin signaling. Chronic immobilization stress blunted the E2-induced increase in Ob-Rb and SOCS3 levels. These results suggest that chronic stress counteracts E2 effects on leptin signaling in the MBH without altering body weight.