Proper nutrition is a key component of athletic performance. Traditionally, endurance athletes have used high-carbohydrate diets to maximize glycogen stores and fuel their performance. Low-carbohydrate, high-fat ketogenic diets, however, have recently gained popularity among endurance athletes to boost performance and fat loss. Athletes assert that adaptation to a low-carbohydrate diet can improve the body’s ability to utilize fat stores by increasing its ketone utilization. The few human studies that analyzed the impact of low-carbohydrate diets on endurance performance show mixed results. However, these studies have very low sample sizes and only examined males. We found that a ketogenic diet can greatly increase endurance running performance in a genetic background- and sex-dependent manner. The study compared forced running performance of five C57BL/6J and FVB/NJ mice of each sex fed ad libitum Western or ketogenic diets for three months. Ketogenic diet-fed C57BL/6J female mice increased their running distance by 89% versus Western diet-fed mice. Male C57BL6/J mice, however, did not have a significant diet effect. FVB/NJ mice of both sexes improved running distance. Ketogenic diet-fed female FVB/NJ mice increased running distance by 70% and males by 49%. The results were independent of fat mass of the mice. Current studies are investigating whether sex-specific hormones are involved in the disparate effects of ketogenic diet on running performance in male and female C57BL/6J mice by ovariectomizing and castrating mice and comparing their forced running phenotype to sham surgery controls. Assessing the role of sex hormones in adaptation to a low-carbohydrate, high-fat diet will help identify the cause of the sex differences on endurance running performance leading to a better understanding of the role of ketogenic diets on exercise performance and the improving ability to identify individuals who might benefit from a ketogenic diet.