Elafin and secretory leukocyte protease inhibitor (SLPI) are anti-protease and anti-microbial molecules present at mucosal surfaces. Both molecules are expressed in the female reproductive tract where they may be involved in innate immune defence. This study examines the role of progesterone in the regulation of SLPI and elafin. Progesterone treatment increases expression of SLPI mRNA and protein in the T47D breast epithelial cell line and this upregulation is attenuated in the presence of the anti-gestogens, RU486 and ZK98734, confirming the involvement of the nuclear progesterone receptor. A putative progesterone response element has been identified in the SLPI promoter. Progesterone also acts in synergy with the proinflammatory cytokines, IL-1beta and TNFalpha, to increase SLPI. In contrast, progesterone treatment has no direct effect on elafin mRNA expression. In summary, progesterone has a differential effect on SLPI and elafin expression and although both vary within the uterus throughout the menstrual cycle, progesterone is likely to contribute to the direct regulation of SLPI in the female reproductive tract even in the presence of inflammatory agents.