We analyzed clinical outcome of patients with an isolated central nervous system lymphoma (CNSL) relapse after systemic non-Hodgkin's lymphoma (NHL). All 23 patients with an isolated secondary CNSL (SCNSL) treated at two institutions from 04/2003-12/2007 were included into this analysis. At cerebral relapse, 15/23 patients were treated with a regimen consisting of high-dose methotrexate (Bonn protocol). After a median follow-up of 6.5 months (range 1-68), 15/23 (65%) patients with SCNSL had relapsed or progressed. HD (high-dose)- methotrexate (MTX) chemotherapy according to the Bonn protocol is effective concerning response rates; however, overall survival of patients with SCNSL seems to be impaired in comparison to relapses in primary CNSL (PCNSL).