<h4>Background</h4>Progressive multiple sclerosis (MS) involves heterogeneous mechanisms, and primary progressive MS without inflammatory activity (PPMS-NA) is poorly understood.<h4>Objective</h4>To characterize the immune-oxidative profile of PPMS-NA and assess plasma IL-6, IL-8, IFNα2, and cerebrospinal fluid (CSF) reactive oxygen species (ROS) as predictors of disability and cognitive decline.<h4>Methods</h4>We conducted a multicenter longitudinal study with two cohorts. The gene discussed is IL6; the disease is multiple sclerosis.