Neuropathological studies of multiple sclerosis (MS) established that diffuse microglia activation with axonal loss in the normal appearing white matter (NAWM) is a main determinant of disease progression. The in vivo study of neuroinflammation and axonal integrity is still challenging. We combined 11C-PBR28 MR-PET with multi-shell diffusion imaging to investigate neuroinflammation and microstructural abnormalities in the NAWM of MS subjects. Results showed evidence of diffuse neuroinflammation accompanied by microstructural diffusion abnormalities with decreased axonal density. The axonal density estimate from the Composite Hindered and Restricted Model of Diffusion was more sensitive than diffusion tensor imaging measures in disclosing axonal damage.