Dietary energy restriction prolongs life-span and enhances immune responsiveness by mechanisms yet to be elucidated. Prostaglandin E2 (PGE2) has a suppressive effect on several parameters of cell-mediated immunity. The effect of energy restriction on splenic PGE2 synthesis in Emory mice was studied. Weanling Emory mice were fed an energy-restricted (R, 71.3 kcal/wk) or control (NR, 90.8 kcal/wk) diet for 11-14 mo. The final weights of R mice were 66% of weights of NR mice (27 +/- 1 vs. 41 +/- 1 g for females and 34 +/- 1 vs. 51 +/- 1 g for males, for R and NR, respectively). NR female mice had higher spleen PGE2 levels than NR male mice (698 +/- 64 vs. 522 +/- 47 ng/mg protein, P = 0.03). In all cases, R mice had less PGE2 than NR mice, and there was no sex-related difference in R mice (418 +/- 39 vs. 698 +/- 64 ng/mg protein in R and NR females, P = 0.001 and 416 +/- 39 vs. 522 +/- 47 ng/mg protein in R and NR males, P = .009). Total spleen PGE2 was also reduced significantly by energy restriction; however, gender differences were not observed in total spleen PGE2 level of NR mice. Thus, 1) spleens from female mice synthesize more PGE2/mg protein than do those from male mice, and 2) dietary energy restriction reduces ex vivo spleen PGE2 synthesis. This phenomenon may contribute to the observed immunostimulatory effect of dietary energy restriction in mice.