Scavenger Receptors (SRs) comprise a structurally diverse group of pattern recognition receptors (PRRs) involved in sensing non-self (microbial-associated molecular patterns) or altered-self ligands. CD5 and CD6 are class I SRs (SR-I) preferentially expressed by lymphoid cells and characterized by the presence of several tandem scavenger receptor cysteine-rich (SRCR) domain repeats. Both receptors interact with diverse microbial struc tures, including tegumental antigens from Echinococcus granulosus sensu lato (s.l.), the cestode parasite responsible for cystic echinococcosis (CE). This is notable as very few PRRs are currently known to detect parasitic helminths and because the infusion of recombinant soluble CD5 and CD6 proteins has shown prophylactic effects in murine secondary CE. Herein, the role of CD5 and CD6 in early immune responses to E. granulosus s.l. tegu mental antigens (PSEx) was analyzed using CD5 (Cd5−/−) and CD6 (Cd6−/−)-deficient mice. Peritoneal B cells and macrophages from wild-type mice displayed specific and dose-dependent PSEx binding, which was impaired in those from Cd5−/− and Cd6−/− mice, supporting direct and/or indirect roles in parasite recognition. Additionally, in vivo exposure of peritoneal exudate cells (PECs) from Cd5−/− and Cd6−/− mice to PSEx showed altered activation profiles, including changes in CD80/CD86 expression, impaired early production of natural polyreactive antibodies, and cytokine shift from a Th1/Th17 to a Th2 profile. These findings strongly support the involvement of CD5 and CD6 receptors in the early immune recognition of E. granulosus s.l. antigens by PECs and influence im muneresponses critical for host resistance, highlighting their relevance in host–parasite interactions.