To date, the circumsporozoite (CS) protein has been implicated in guiding malaria sporozoites to the liver [Cerami et al., Cell 70, 1992, 1021-1033]. Here we show that shortly after invasion, P. berghei and P. yoelii sporozoites lie free in the invaded cell and release considerable amounts of CS protein into the cytoplasm. The intracytoplasmic deposition of CS protein begins during the attachment of the sporozoite to the host cell surface and reaches its peak during the first 4-6 h after invasion. Initially, the CS protein spreads over the entire cytoplasm of the infected cell where it interacts with cytosolic as well as endoplasmic reticulum-associated ribosomes. During the subsequent development of the parasites to exoerythrocytic forms, the CS protein binding becomes gradually restricted to ribosomes lining the outer membrane of the nuclear envelope of the host cell. The distribution pattern of the parasite-released CS protein in the host cell cytoplasm is independent of the permissiveness of the host cell for the development of the parasites to exoerythrocytic forms. It requires neither the host cell metabolism nor does it involve the endocytotic machinery. Recombinant P. falciparum CS protein interacts with RNAse-sensitive sites on endoplasmic reticulum-associated ribosomes as shown by microinjection and immunoelectron microscopy. The generalized interaction of the CS protein with host cell ribosomes suggests that the CS protein has an intracellular function during the hepatic phase in the life cycle of Plasmodium and may also explain the generation of a CD8+ T cell response in the course of rodent malaria infections.