Background There is evidence of sex differences in the physiology of endurance exercise, yet most of the advice and guidelines on training, racing, nutrition, and recovery for ultramarathons are based on research that has largely excluded female athletes. The objective was therefore to review the current knowledge of sex differences in ultramarathon runners and determine if sufficient evidence exists for providing separate guidelines for males and females. Methods This systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Three databases were searched for studies investigating differences in elite and recreational male and female ultramarathon runners. Studies were included if they compared males and females and looked at outcomes relating to the performance or health of ultramarathon runners. The quality of the included studies was determined using the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach. Results The search strategy identified 45 studies that met the inclusion criteria. Most studies were observational in design, with only three papers based on randomised controlled trials. The overall quality of the evidence was low. Sex differences in the predictors of ultramarathon performance; physiological responses to training, racing, and recovery; chronic and acute health issues; and pacing strategies were found. There were areas with contradictory findings, and very few studies examined specific interventions. Conclusion The results from this review suggest that the development of sex-specific guidelines for ultramarathon coaches and athletes could have a significant effect on the performance and health of female runners. At present, there is insufficient high-quality evidence on which to formulate these guidelines, and further research is required.