Granulomatous inflammation is key to the pathogenesis of many infectious diseases, including hepatic schistosomiasis. The granulomas that form around schistosome eggs trapped in the liver of infected hosts were thought to be induced primarily, if not exclusively, by egg Ags. We now show that the maturation of adult worms, before the production of eggs, primes local immune responses key to granuloma formation. When parasite eggs are injected into the livers of naive animals, only a minimal, nongranulomatous, inflammatory response results. However, if eggs are injected into the livers of mice previously infected with single-sex adult worms, granuloma formation is restored. Granuloma formation is also restored if mice are presensitized with adult worm homogenates or with eggs themselves before egg injection into the liver. These sensitization studies confirm that an Ag or Ags are shared between different stages of the schistosome life cycle and that immune priming by these Ag(s) is necessary for hepatic granuloma formation. Models of infection that isolate the effects of worms from those of eggs confirm that each of these life cycle stages induces a unique pattern of cytokine expression. Hepatic expression of TNF-alpha, a major cytokine signal for granuloma formation, is a reaction to adult worms, not eggs. TNF-alpha may mediate immune priming necessary for granuloma development since injection of purified TNF-alpha alone restores formation of granulomas in the livers of naive mice injected with eggs.