Inbred mice carrying mutations in ankyrin and/or spectrin synthesis and assembly were studied for their ability to support the growth of the rodent malarias, Plasmodium chabaudi adami and P. berghei, in vivo. Mice carrying the nb/nb (normoblastosis) mutation which do not synthesize ankyrin and therefore also have a deficiency in membrane-bound spectrin, were refractory to P. chabaudi adami, which invades mature erythrocytes and to P. berghei, which invades reticulocytes. Similarly, sph/sph mice which do not synthesize the alpha chain of spectrin but do synthesize ankyrin, were also resistant to both parasites. The heterozygote for the nb defect (nb/+) exhibited a diminution of parasitaemia. We conclude that the host cell spectrin may be necessary for the invasion and/or growth of rodent malarial parasites.