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Cystic echinococcosis (CE) is a worldwide neglected zoonotic disease caused by infection with the larval stage of the tapeworm Echinococcus granulosus sensu lato (E. granulosus s.l.), which predominantly resides in the liver accompanied by mild inflammation. Macrophages constitute the main cellular component of the liver and play a central role in controlling the progression of inflammation and liver fibrosis. However, the role of hepatic macrophages in the establishment and growth of hydatid cysts in the liver during E. granulosus sensu stricto (E. granulosus s.s.) infection has not been fully elucidated. Here, we showed that CD68+ macrophages accumulated in pericystic areas of the liver and that the expression of CD163, a marker of anti-inflammatory macrophages, was more evident in active CE patients than in inactive CE patients. Moreover, in a mouse model of E. granulosus s.s. infection, the pool of hepatic macrophages expanded dramatically through the attraction of massive amounts of monocyte-derived macrophages (MoMFs) to the infection site. These infiltrating macrophages preferentially polarized toward an iNOS+ proinflammatory phenotype at the early stage and then toward a CD206+ anti-inflammatory phenotype at the late stage. Notably, the resident Kupffer cells (KCs) predominantly maintained an anti-inflammatory phenotype to favor persistent E. granulosus s.s. infection. In addition, depletion of hepatic macrophages promoted E. granulosus s.s. larval establishment and growth partially by inhibiting CD4+ T-cell recruitment and liver fibrosis. The above findings demonstrated that hepatic macrophages play a vital role in the progression of CE, contributing to a better understanding of the local inflammatory responses surrounding hydatid cysts and possibly facilitating the design of novel therapeutic approaches for CE. Author summary: Cystic echinococcosis (CE) is one of the neglected zoonoses caused by Echinococcus granulosus s.l. larvae and is a worldwide public health problem. Previous study showed that CE is usually characterized by mild local inflammation, indicating that E. granulosus s.l. can control liver inflammation to shape an 'immunosuppressive' microenvironment, a balance between pro- and anti-inflammatory responses to maintain immune homoeostasis during persistent infection. Here, by combining data from human CE samples and animal models, we found that hepatic macrophages are involved in the control of liver inflammation to favor persistent E. granulosus s.s. infection. The pool of hepatic macrophages expanded dramatically at the early stage through the attraction of massive amounts of MoMFs that preferentially initially polarized toward a proinflammatory phenotype and then toward an anti-inflammatory phenotype to favor persistent infection at the late stage after infection. Depletion of hepatic macrophages accelerated hydatid cyst establishment and growth by inhibiting CD4+ T-cell infiltration and liver fibrosis during E. granulosus s.s. infection. Our findings contribute to a better understanding of the local microenvironment in CE and possibly facilitate the design of novel therapeutic approaches for CE that target hepatic macrophages. [ABSTRACT FROM AUTHOR]