Progesterone based contraceptives are the most commonly used hormone contraceptives worldwide. Mounting evidence suggests that some of these progesterone based contraceptives, particularly depo-medroxyprogesterone acetate (DMPA), may enhance susceptibility of women to HIV acquisition. Although it is known that certain types of progesterone based contraceptives do alter immunity in the female reproductive tract (FRT), the exact mechanism of this is yet to be determined. We have discovered and characterised a novel member of the anti-viral type I interferon (IFN) family, called IFN epsilon (IFNε), which is highly expressed in the FRT (1). It is an important mediator of local immune responses against pathogens, including viral sexually transmitted infections (STIs), due to its direct anti-viral action on the FRT. Instead of being regulated in response to pathogens, like other type I IFNs, IFNε is regulated in response to hormones. Interestingly, IFNε expression is lowest during the progesterone high, secretory phase of the menstrual cycle, when women are known to be more vulnerable to viral infection. Our evidence suggests that IFNε expression is directly repressed in response to progesterone and we are currently investigating the hormonal regulation of IFNε expression in the lower and upper FRT in humans and how this may be altered when women are on hormone based contraceptives.