Ultra-endurance has been defined as any exercise bout that exceeds 6 h. A number of exceptional, record-breaking performances by female athletes in ultra-endurance sport have roused speculation that they might be predisposed to success in such events. Indeed, while the male-to-female performance gap in traditional endurance sport (e.g., marathon) remains at ~ 10%, the disparity in ultra-endurance competition has been reported as low as 4% despite the markedly lower number of female participants. Moreover, females generally outperform males in extreme-distance swimming. The issue is complex, however, with many sports-specific considerations and caveats. This review summarizes the sex-based differences in physiological functions and draws attention to those which likely determine success in extreme exercise endeavors. The aim is to provide a balanced discussion of the female versus male predisposition to ultra-endurance sport. Herein, we discuss sex-based differences in muscle morphology and fatigability, respiratory-neuromechanical function, substrate utilization, oxygen utilization, gastrointestinal structure and function, and hormonal control. The literature indicates that while females exhibit numerous phenotypes that would be expected to confer an advantage in ultra-endurance competition (e.g., greater fatigue resistance, greater substrate efficiency, and lower energetic demands), they also exhibit several characteristics that unequivocally impinge on performance (e.g., lower O2-carrying capacity, increased prevalence of GI distress, and sex-hormone effects on cellular function/injury risk). Crucially, the advantageous traits may only manifest as ergogenic in the extreme endurance events which, paradoxically, are those that females less often contest. The title question should be revisited in the coming years, when/if the number of female participants increases.