Schistosomiasis remains a major health concern in parts of China and the Philippines, where water buffaloes are a major source of human transmission. An effective livestock vaccine could simultaneously improve animal health and reduce human infection. Novel effective vaccine molecules are required, especially against the migrating larvae, which are considered an ideal target for vaccination. Here we examined the local immune response induced by the migrating larvae in the natural host, the water buffalo, in order to firstly identify novel larval-specific antigens recognised by the buffalo, and secondly to establish the type of immune response the larvae elicit. To this effect, cells were cultured from lymph nodes draining larval infection sites (skin and lung), and the secreted antibody was collected. The antibody response in skin lymph nodes from infected buffalo produced significant amounts of antibody, compared to control animals, and is being used to discover novel larval-specific vaccine targets. The type of response the larvae elicit in the buffalo was investigated by histological examination of target tissues, and cytokine analysis of cultured LN cells and PBMCs. A strong inflammatory response was observed in skin tissues shortly after infection, as well as increased IL-4 and IL-10 production in draining lymph nodes, indicative of a type-2 immune response. This study is the first to investigate the immune response of the water buffalo against migrating larvae and is anticipated to provide new targets for generating a transmission-blocking vaccine.