Experimental severe malaria (ESM; also known as experimental cerebral malaria) is an acute lethal syndrome caused by infection with Plasmodium berghei ANKA and associated with coma and other neurological manifestations in mice. Various inbred strains of mice exhibit differences in susceptibility to the development of ESM. For example, C57BL/6 mice are highly susceptible and DBA/2 mice are relatively resistant. We report here the results of a genomewide scan for host genomic regions that control resistance to ESM in DBA/2 mice using an F(2) intercross population of susceptible and resistant strains. A region of mid-chromosome 18 was found to be a major determinant of resistance to ESM.