Technical Abstract: Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. Using Retnla deficient (-/-) mice and three helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni (Sm) is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Retnla (-/-) mice chronically infected with (Sm) displayed significant increases in granulomatous inflammation in the liver and augmented development of fibrosis and progression to hepatosplenic disease. Finally, Retnla (-/-) mice infected with the GI nematode parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla (-/-) mice developed stronger Th2 responses, which could be reversed by exogenous rRelma treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while other experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses.