Purpose: The aim of this study was to determine the relationship between relative glucose uptake and MRI T₂ changes in skeletal muscles following resistance exercise using simultaneous PET/MRI scans. Methods: Ten young healthy recreationally active men (age 21 – 28 years) were injected with ¹⁸F-FDG while activating the quadriceps of one leg with repeated knee extension exercises followed by hand-grip exercises for one arm. Immediately following the exercises, the subjects were scanned simultaneously with ¹⁸F-FDG PET/MRI and muscle groups were evaluated for increases in ¹⁸F-FDG uptake and MRI T₂ values. Results: A significant linear correlation between ¹⁸F-FDG uptake and changes in muscle T₂ (R² = 0.71) was found. for both small and large muscles and in voxel to voxel comparisons. Despite large intersubject differences in muscle recruitment, the linear correlation between ¹⁸F-FDG uptake and changes in muscle T₂ did not vary among subjects. Conclusion: This is the first assessment of skeletal muscle activation using hybrid PET/MRI and the first study to demonstrate a high correlation between ¹⁸F-FDG uptake and changes in muscle T₂ with physical exercise. Accordingly, it seems that changes in muscle T₂ may be used as a surrogate marker for glucose uptake and lead to an improved insight into the metabolic changes that occur with muscle activation. Such knowledge may lead to improved treatment strategies in patients with neuromuscular pathologies such as stroke, spinal cord injuries and muscular dystrophies.