Observations were made on the development of immunity to Schistosoma mansoni in baboons using both homologous and heterologous systems. The baboons were immunized by either (a) a single exposure to cercariae of the homologous species S. mansoni, or (b) 1-2 exposures to cercariae of either a S. rodhaini/S. mansoni hybrid or a S. mattheei/S. haematobium hybrid, or (c) repeated exposure to the cercariae of S. rodhaini or S. bovis. Baboons immunized with 500 cercariae of the homologous parasite developed partial immunity to reinfection, as did the baboons immunized with multiple exposures to the heterologous cercariae of S. rodhaini and S. bovis, although these parasites produced neither adult worms nor eggs in the baboons. The hybrids gave rise to well-established adult worm infections, but produced less immunity, even though the S. rodhaini/S. mansoni hybrid was genetically very similar to S. mansoni. These results indicate that adult worms are not essential to produce a considerable degree of immunity to reinfection, which can be engendered by the earlier stages of the parasites. However, none of the immune responses prevented egg deposition in the tissues, and considerable pathological changes resulted from the challenge infection. These observations suggest that although heterologous infections show some promise as immunizing agents, further studies are needed of the pathological changes resulting from their use.