Multiple sclerosis (MS) is characterized by lesions with inflammatory infiltration, demyelination and axonal damage in the CNS white matter that correlates with the extent of disease disability. Knowledge of up-regulatory triggers of neuroprotective pathways in the CNS is essential for the development of the next generation of disease therapies. Recent studies have suggested a neuroprotective activity of the lesion-infiltrating immune cells. We studied the secretion of brain-derived neurotrophic factor (BDNF) from the immune cells of untreated patients with relapsing remitting (RR) MS with mild to moderate disability and sought immune factors that regulate the BDNF levels and affect the survival of neuronal cells in vitro. We found lower than normal secreted levels of BDNF from the immune cells of these patients. The normal effect of CD40 stimulation that up-regulates BDNF secretion levels and induces neuroprotection was absent in the MS patients, while the expression of CD40 on their monocytes was elevated. The failure of BDNF availability from immune cells in patients with RR-MS and the loss of a neuroprotective effect by these cells may be related to a more widespread phenomenon of deviated immunity in MS, and may be linked to the continuous CNS neuronal tissue loss during the course of this disease.