Previous in vitro studies have shown that CD36 participates in cellular fatty acid (FA) uptake. In vivo evidence for a physiologic role of CD36 in this process is poor and mostly obtained in animals. To examine the metabolic role of human CD36, we performed a glucose loading test for normals (n = 16) and subjects with CD36 deficiency, both Type I (n = 5) and Type II (n = 16). After 30 min, FA levels had fallen by 60.1% in normals but by only 31.7% in Type II deficiency (P <0.01 vs. normals) and 16.5% in Type I deficiency which remained significantly higher than the other two groups out to 2 h. Further, changes in triglyceride and glucose metabolism were observed in the both types of CD36 deficiency. Impaired fast FA clearance by muscle and consequently increased hepatic FA uptake seem to underlie these changes. We conclude that human CD36 deficiency causes systemic metabolic changes.