We report a case of multiple sclerosis-associated fulminant tumefactive demyelinating lesion (TDL) with the special feature of delayed humoral immune response. Plasma exchange (PE) yielded significant benefit in two consecutive steroid-unresponsive relapses, while signs of an intrathecal B-cell response were only present 2 years later at the second relapse. Remission was achieved and sustained thereafter with natalizumab. Our case indicates that PE might be a therapeutic option even when the B-cell response is not fully developed. This delay in the development of a humoral immune response may reflect the step-wise B-cell colonization of the CNS and represent an attractive therapeutic window of opportunity.