Summary It is well known that sleep loss is associated with significant short- and long-term health consequences, but to date the impact of sex differences in response to sleep loss are poorly understood. We and others have shown that women have greater neurobehavioral performance impairment than men when exposed to one night of acute sleep loss. Furthermore, when this effect is examined separately by menstrual cycle phase, women in the follicular phase exhibit greater impairment compared to both men and women during the luteal phase, suggesting a possible endocrine mechanism. Indeed, we have shown that these differences in performance may be driven by sex-steroid-mediated changes in core body temperature (CBT), specifically involving the ratio of progesterone (P4) to estradiol (E2) between the follicular and luteal phases. These findings have important implications for understanding the interactions of sleep loss and female sex hormones on neurobehavioral performance and other health consequences. An important open question, however, is how these menstrual-phase-dependent differences impact performance under more realistic patterns of chronic sleep loss. Millions of women routinely obtain less than the recommended 7-9 hours of sleep per night during the week and attempt to catch up on sleep on the weekend. In men, we have shown that any apparent improvement during such recovery sleep is transient, and that subsequent sleep loss results in more accelerated deterioration in performance. It is unknown how this variable pattern of chronic sleep loss and recovery sleep impacts performance in women during the follicular and luteal phases of the menstrual cycle. The proposed work will fill this important gap in knowledge. In our proposed 11-day inpatient study, healthy premenopausal women will be randomized to either chronic variable sleep deficiency (with a repeated pattern of two nights of 3 hours time-in-bed followed by one night of 10 hours time- in-bed, equivalent to our prior study in mean) or a sleep satiation control (10 hours time-in-bed throughout) during either the follicular or luteal phase of their menstrual cycle. This protocol will allow us to quantify both the impact of chronic variable sleep deficiency on neurobehavioral performance in women and differences in the response to chronic variable sleep loss across the menstrual cycle. We will also investigate the role of CBT, P4, and E2 in mediating these responses. As an exploratory analysis, we will also evaluate the impact of chronic variable sleep loss on E2 and P4 levels to investigate the effect of insufficient sleep on circulating levels of female sex hormones across the menstrual cycle. There is immediate