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Multifocal necrotizing leukoencephalopathy, characterized by multiple microscopic foci of necrosis involving the white matter of the pons, has been described mainly after chemotherapy or radiotherapy for brain cancer and in HIV infection. The role of circulating cytokines has been suggested but remains to be assessed.Prospective case series.A 26-bed general medical intensive care unit at a university hospital.Septic shock patients.In three patients who died from septic shock, careful postmortem examination of the brain was performed, including studies of neuronal apoptosis and cytokine expression.In one patient, typical lesions of multifocal necrotizing leukoencephalopathy were seen. As compared with control 1 and control 2 who did not have multifocal necrotizing leukoencephalopathy, marked lesions of the pons, including vacuolization, apoptosis, microglial activation, and expression of tumor necrosis factor-α and interleukin-1β, were observed in the case. Simultaneously, case 1 had markedly increased circulating levels for tumor necrosis factor-α, interleukin-1β, interleukin-6, interleukin-8, interleukin-10, soluble tumor necrosis factor receptor II, and for interleukin-1 receptor antagonist.Septic shock is a newly described cause of multifocal necrotizing leukoencephalopathy, probably mediated by an excessive systemic inflammatory response.