Diffusion‐weighted imaging has been largely used to detect and quantify early degenerative changes in patients with multiple system atrophy, but progression of neurodegeneration has been poorly investigated. We performed a serial diffusion‐weighted imaging study in a population of multiple system atrophy patients and analyzed the evolution of diffusion properties in striatal and extrastriatal brain regions. Diffusion‐weighted imaging was obtained in 11 multiple system atrophy patients at baseline and after a follow‐up of 11.7 ± 1.2 months, and Trace (D) changes in different brain regions were correlated with disease duration and severity. A significant increase in Trace (D) was observed at follow‐up in the putamen (P < .001), pons (P = .003), cerebellar white matter (P = .03), thalamus (P = .013), and frontal white matter (P = .021). Both Unified Multiple System Atrophy Rating Scale Part II and Unified Parkinson's Disease Rating Scale Part III scores significantly increased at follow‐up (P = .003), but percent changes of Unified Parkinson's Disease Rating Scale Part III and Unified Multiple System Atrophy Rating Scale Part II did not correlate with percent changes of Trace (D) values in any brain region. This longitudinal study provides new insights into the progression of neurodegeneration in different brain regions in multiple system atrophy. Our results confirm that abnormal diffusivity in the putamen is sensitive to change over time in multiple system atrophy patients and show for the first time a progression of Trace (D) alterations in specific extrastriatal regions. Diffusivity changes in these regions may be useful for monitoring disease progression even after a short follow‐up period. © 2011 Movement Disorder Society