Background: Sleep deprivation and fatigue have been associated with medical errors, clinical performance decrements, and reduced quality of life for both practicing physicians and medical students. Greater understanding of the impact of sleep quantity on clinical reasoning could improve patient care. The purpose of our pilot study was to examine relationships between clinical reasoning (assessed by functional magnetic resonance imaging) and sleep time (measured in different ways by actigraphy) while answering multiple-choice questions (MCQs) from licensing agencies. Methods: Residents and faculty were administered a clinical reasoning exercise (MCQs from licensing bodies) during functional magnetic resonance imaging. Usual sleep patterns were sampled with actigraphy. Covariate analysis was used to examine the relationship between sleep duration (mean sleep, minimum sleep, maximum sleep) and brain activity during clinical reasoning (solving MCQs from licensing bodies). Results: The mean sleep time over the duration of monitoring for the group was 7.19 hours (SD 0.66) with a range of 6.1 to 8.1 hours (internal medicine faculty 7.1 hours, SD 0.41; internal medicine residents 7.27 hours, SD 0.92). There was a negative relationship between activation in the prefrontal cortex and minimum sleep time while reflecting on MCQs. Conclusion: Our findings provide evidence that the quantity of sleep can modulate brain activity while completing a clinically meaningful task that should be confirmed in larger studies. Our findings suggest that the construct of sleepiness may be more complex than appreciated by many and that the most important of these sleep measures in terms of outcomes remains to be determined.