Fatigue sustained during short-term, high-intensity exercise in humans is associated with the inability of skeletal muscle to maintain a high rate of anaerobic ATP production from phosphocreatine hydrolysis. Ingestion of creatine monohydrate at a rate of 20 g/d for 5-6 d was shown to increase the total creatine concentration of human skeletal muscle by approximately 25 mmol/kg dry mass, some 30% of this in phosphorylated form as phosphocreatine. A positive relation was then shown between muscle creatine uptake and improvements in performance during repeated bouts of maximal exercise. However, there is no evidence that increasing intake > 20-30 g/d for 5-6 d has any potentiating effect on creatine uptake or performance. In individuals in whom the initial total creatine concentration already approached 150 mmol/kg dry mass, neither creatine uptake nor an effect on phosphocreatine resynthesis or performance was found after supplementation. Loss of ATP during heavy anaerobic exercise was found to decline after creatine ingestion, despite an increase in work production. These results suggest that improvements in performance are due to parallel improvements in ATP resynthesis during exercise as a consequence of increased phosphocreatine availability. Creatine uptake is augmented by combining creatine supplementation with exercise and with carbohydrate ingestion.