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Two isolates of Schistosoma mansoni from Puerto Rico and Egypt were examined to determine if there were differences in surface antigens of the schistosomulum and to assess the ability of the two isolates to induce protection against one another in vivo. Immune mouse and human patient antisera recognized the same antigens on the schistosomulum surface of both isolates. However, mice immunized with schistosomula-released products from the Egyptian isolate recognized an additional antigen of Mr 13K on the Egyptian schistosomulum surface which was not present in the Puerto Rican isolate. In quantitative radioimmunoassay, sera from mice vaccinated with irradiated Egyptian cercariae bound more strongly to Egyptian schistosomula than to Puerto Rican parasites. Both isolates cross-protected against each other, but mice were less immune to challenge with Egyptian cercariae after being immunized with Puerto Rican irradiated cercariae. There was no difference in immunity to challenge when Egyptian irradiated cercariae were used to immunize. Although this evidence suggested some heterogeneity within the Egyptian isolate, cloned cercariae of the Egyptian isolate did not vary in their ability to cross-protect against each other. Furthermore, antisera from mice immunized with clones of Egyptian cercariae recognized the same schistosomulum surface antigens. The results reported here indicate that although there were small differences between the two isolates the major surface antigens are conserved.