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Background: Liver fluke infection of livestock causes economic losses of over US$ 3 billion worldwide per annum. The disease is increasing in livestock worldwide and is a re-emerging human disease. There are currently no commercial vaccines, and only one drug with significant efficacy against adult worms and juveniles. A liver fluke vaccine is deemed essential as short-lived chemotherapy, which is prone to resistance, is an unsustainable option in both developed and developing countries. Protein superfamilies have provided a number of leading liver fluke vaccine candidates. A new form of glutathione transferase (GST) family, Sigma class GST, closely related to a leading Schistosome vaccine candidate (Sm28), has previously been revealed by proteomics in the liver fluke but not functionally characterised. Methodology/Principal Findings: In this manuscript we show that a purified recombinant form of the F. hepatica Sigma class GST possesses prostaglandin synthase activity and influences activity of host immune cells. Immunocytochemistry and western blotting have shown the protein is present near the surface of the fluke and expressed in eggs and newly excysted juveniles, and present in the excretory/secretory fraction of adults. We have assessed the potential to use F. hepatica Sigma class GST as a vaccine in a goat-based vaccine trial. No significant reduction of worm burden was found but we show significant reduction in the pathology normally associated with liver fluke infection. Conclusions/Significance: We have shown that F. hepatica Sigma class GST has likely multi-functional roles in the host-parasite interaction from general detoxification and bile acid sequestration to PGD synthase activity. Author Summary: Combating neglected parasitic diseases is of paramount importance to improve the health of human populations and/or their domestic animals. Uncovering key roles in host-parasite interactions may support the vaccine potential portfolio of a parasite protein. Fasciola hepatica causes global disease in humans and their livestock but no commercial vaccines are available. Members of the Sigma class glutathione transferase (GST) family have long been highlighted as vaccine candidates towards parasitic flatworms. To this end, a Sigma class GST is currently undergoing phase II clinical trials to protect against infection from the schistosomes. In this study we characterise the protein from F. hepatica following four work pathways that 1) confirm its designation as a Sigma class GST using substrate profiling, 2) assess prostaglandin synthase activity and its effect on host immune cells, 3) localise the Sigma GST within adult fluke and between ontogenic stages and 4) measure its potential as a vaccine candidate. The work presented here shows F. hepatica Sigma class GST to have key host-parasite roles and we suggest, warrants further investigation for inclusion into vaccine formulations. [ABSTRACT FROM AUTHOR]