The sleep-wake cycle and circadian rhythmicity both contribute to brain function, but whether this contribution differs between men and women and how it varies across cognitive domains and subjective dimensions has not been established. We examined the circadian and sleep-wake-dependent regulation of cognition in 16 men and 18 women in a forced desynchrony protocol and quantified the separate contributions of circadian phase, prior sleep, and elapsed time awake on cognition and sleep. The largest circadian effects were observed for reported sleepiness, mood, and reported effort; the effects on working memory and temporal processing were smaller. Although these effects were seen in both men and women, there were quantitative differences. The amplitude of the circadian modulation was larger in women in 11 of 39 performance measures so that their performance was more impaired in the early morning hours. Principal components analysis of the performance measures yielded three factors, accuracy, effort, and speed, which reflect core performance characteristics in a range of cognitive tasks and therefore are likely to be important for everyday performance. The largest circadian modulation was observed for effort, whereas accuracy exhibited the largest sex difference in circadian modulation. The sex differences in the circadian modulation of cognition could not be explained by sex differences in the circadian amplitude of plasma melatonin and electroencephalographic slow-wave activity. These data establish the impact of circadian rhythmicity and sex on waking cognition and have implications for understanding the regulation of brain function, cognition, and affect in shift-work, jetlag, and aging.cognition | biological rhythms | gender | slow wave sleep | melatonin C ircadian rhythms are generated by a set of core "clock" genes and are present in nearly every cell of the body and brain (1). These local clocks and rhythms are synchronized by neural and endocrine pathways originating from the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) (2, 3). In addition, the timing of behaviors such as food intake and sleep and associated changes in local and systemic cues contribute to the temporal organization in peripheral tissues outside the SCN (4, 5). In view of the pervasiveness of circadian rhythms, it is not surprising that they affect many aspects of physiology, behavior, and cognition in health and in disease. Indeed, circadian abnormalities have been implicated in disorders of sleep, mood, and cognition (6), in deleterious responses to shift work (7), depression (8), and Alzheimer's disease (9). The prevalence of most of these disorders is higher in women than in men (10), and their impact on psychological functions and quality of life of patients differs between the sexes (11).Women are underrepresented in both circadian and sleep research (12), although sex differences in human circadian and sleep characteristics are emerging from the few studies that contrast men and women. (Note: Throughout thi...