Study Objectives: To contrast the effects of total sleep deprivation (TSD) on executive and non-executive function in volunteers homozygous for either the short or long variant of a variable number tandem repeat polymorphism in PERIOD3, which is a genetic marker for susceptibility to the negative effect of sleep loss on waking performance. Design: Following two laboratory nights of baseline sleep, both groups underwent an approximately 40-hour constant routine, performing brief tests of executive, memory, attention, and motor function every 2 hours. Setting: Clinical Research Centre Participants: Fourteen PER34/4 (homozygotes for shorter variant of the gene) and 10 PER35/5 (homozygotes for longer variant) healthy, young adults (mean 25.0 ± 1.0 years). Interventions: Total sleep deprivation (∼ 40 hours) following baseline sleep. Measurements and Results: Hormonal assays established that melatonin levels, which reflect circadian phase, reached their midpoint around 04:00 in both genotypes. Cognitive performance deteriorated across the night, and was similar for both genotypes throughout, except 2-4 h after the midpoint of the melatonin rhythm. Only at this time-point and only on tests of executive function (e.g., 3-back, paced visual serial addition task) did PER35/5 participants perform reliably worse. Covariance analyses controlling for genotype dependent differences in homeostatic sleep pressure derived from principal component analysis of baseline sleep latency, slow wave sleep and wake after sleep onset largely removed these early morning differences in executive function. Conclusions: This PER3 polymorphism differentially influences the effects of sleep deprivation on executive and non-executive function in the early morning. These effects appear to be mediated through homeostatic sleep pressure.