Studies in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) suggest that peripheral monocyte-derived cells (MDCs) are instrumental for disease initiation. MDCs, however, are plastic, and may exert various functions once in the central nervous system (CNS) for prolonged periods. Furthermore, the long-term effect of MDC depletion on continuing axon loss is not known. We show that long-lasting depletion of MDCs, after onset of EAE clinical deficits, is accompanied by decreased CNS infiltration by pathogenic T lymphocytes. Although this treatment does not reverse clinical disease, it prevents worsening of neurological deficits and long-term axonal loss.