Resistance to schistosomiasis in mice can be acquired either specifically, by primary infection with Schistosoma mansoni, or nonspecifically, by treatment with a variety of unrelated agents such as bacille Calmette-Guérin. Several immunoadjuvants related to mycobacteria were examined for their ability to induce resistance to schistosomiasis. Natural cord factor (6,6'-trehalose dimycolate), a 100-carbon synthetic cord factor analogue, and dipalmitate trehalose induced significant protection. Trehalose dibehenate and muramyl dipeptide did not induce consistent protection. Since protection acquired by primary schistosomal infection or by any of these potentiating agents is partial, their possible additive effect was evaluated. The resistance of mice with schistosomiasis that were injected with trehalose dipalmitate and challenged with schistosomal cercariae was increased, as assayed by recovery of schistosomula from the lungs and of adult worms from the portal system. Thus, these synthetic adjuvants not only induce partial protection against schistosomiasis, but also significantly enhance acquired immunity in mice with primary infections.