Abstract The mouse Breast Regression Protein 39 (BRP39; Chi3l1) is a chitinase like protein but lacks enzymatic activity. Recently it was shown that mice lacking BRP39 displayed significantly impaired Th2 response during allergic airway disease. We sought to examine if the absence of BRP39 would affect the generation of protective and pathogenic Th2 responses following helminth infections. In a model of Schistosoma mansoni egg induced pulmonary granuloma formation, naive BRP39KO animals developed weaker Th2 response upon egg embolization. The Th2 responses were restored to WT levels if pulmonary granulomas were elicited in antigen primed (secondary granuloma) animals. However, the size of secondary egg granulomas remained significantly smaller in the KO animals, suggesting a role for BRP39 in regulation of pulmonary granuloma response. In contrast, following infection with S. mansoni cercariae, BRP39KO animals manifested larger hepatic granulomas and significantly exacerbated liver fibrosis and showed an increased prevalence of CD4+ cells making IL-5 and IL-13 among the granuloma leukocytes. Furthermore, Nippostrongylus brasiliensis infected BRP39KO mice displayed no defect in worm expulsion suggesting normal Th2 response in the gut. Thus, these studies reveal that the defectiveTh2 response in the absence of BRP39 is a transient phenomenon and introduce the possibility that BRP39 could negatively regulate Th2 responses in a chronic setting and in a tissue specific manner.