Schistosoma haematobium is responsible for two-thirds of the world's 200 million to 400 million cases of human schistosomiasis. It is a group 1 carcinogen and a leading cause of bladder cancer that occurs after years of chronic inflammation, fibrosis, and hyperproliferation in the host liver. The coevolution of blood flukes of the genus Schistosoma and their human hosts is paradigmatic of long-term parasite development, survival, and maintenance in mammals. However, the contribution of host genes, especially those discrete from the immune system, necessary for parasite establishment and development remains poorly understood. This study investigated the role of metastasis-associated protein-1 gene (Mta1) product in the survival of S. haematobium and productive infection in the host. Using a Mta−1 null mouse model, here we provide genetic evidence to suggest that MTA1 expression positively influences survival and/or maturation of schistosomes in the host to patency, as we reproducibly recovered significantly fewer S. haematobium worms and eggs from Mta1−/− mice than wild−type mice. In addition, we found a distinct loss of cytokine interdependence and aberrant Th1 and Th2 cytokine responses in the Mta1−/− mice compared to age-matched wild-type mice. Thus, utilizing this Mta1-null mouse model, we identified a distinct contribution of the mammalian MTA1 in establishing a productive host–parasite interaction and thus revealed a host factor critical for the optimal survival of schistosomes and successful parasitism. Moreover, MTA1 appears to play a significant role in driving inflammatory responses to schistosome egg–induced hepatic granulomata reactions, and thus offers a survival cue for parasitism as well as an obligatory contribution of liver in schistosomiasis. Conclusion: These findings raise the possibility to develop intervention strategies targeting MTA1 to reduce the global burden of schistosomiasis, inflammation, and neoplasia. (HEPATOLOGY 2011;)