OBJECTIVE: The purpose of our study was to test the hypothesis that the apparent diffusion coefficient (ADC) of normal-appearing white matter increases with advancing age. SUBJECTS AND METHODS: We selected 38 patients with normal MR imaging findings from 332 patients undergoing clinical MR imaging. Diffusion-weighted MR imaging was performed with diffusion gradients applied in three orthogonal directions. For each patient, the average ADC on trace-weighted diffusion images of white matter at prespecified regions of interest and at the thalamus were compared with the patient's age. RESULTS: For the white matter, ADC sorted by patient age in decades increased with advancing age. Patients at least 60 years old had significantly higher ADC (0.769 +/- 0.019 mm(2)/sec x 10(-3)) than patients less than 60 years old (0.740 +/- 0.013 mm(2)/sec x 10(-3)) (p < 0.001). Comparison of individual white matter ADC and age showed a significant increase with advancing age (p < 0.0001). For the thalamus, the average ADC among patients at least 60 years old (0.766 +/- 0.015 mm(2)/sec x 10(-3)) exceeded the average ADC for patients less than 60 years old (0.745 +/- 0.022 mm(2)/sec x 10(-3)) (p < 0.05). However, comparison of individual thalamic ADC and patient ages, although showing a trend to higher ADC with increasing age, did not reach statistical significance (p = 0.06). CONCLUSION: Advancing age is associated with a small but statistically significant increase of water diffusibility in human white matter. A similar trend was present in the thalamus. These increases may reflect mild structural changes associated with normal aging.