The pathological hallmark of chronic multiple sclerosis includes focal demyelination, gliosis, inflammation and axonal injury. There is limited information on whether these pathological features differ across the clinical phenotypes of the disease (relapsing-remitting, secondary progressive, and primary progressive). This review will focus on the pathological aspects of PPMS and pathogenic implications. A better understanding of the differences in PPMS pathology and pathogenesis will lead to more effective treatment strategies.