Large peritoneal macrophages (LPMs) play a role as gatekeepers of peritoneal homeostasis by providing a first line of defense against pathogens. A third of the LPMs express the surface receptor VSIG4, but it is unclear whether these cells differ from their VSIG4-negative counterparts and perform dedicated functions. We demonstrate that VSIG4, but not VSIG4, LPMs are in the majority derived from embryonal precursors, and their occurrence is largely independent of sex and microbiota but increases with age. Although their transcriptome and surface proteome are indistinguishable from VSIG4 LPMs at steady-state, VSIG4 LPMs are superior in phagocytosing S. aureus bioparticles and colorectal carcinoma (CRC) cells. Anti-VSIG4 nanobody constructs that are ADCC-enabled allowed a selective elimination of the VSIG4 LPM subset without affecting overall LPM abundance. This strategy uncovered a role for VSIG4 LPMs in lowering the first peak of parasitemia in a Trypanosoma brucei brucei infection model and in reducing CRC outgrowth in the peritoneal cavity, a prime metastatic site in CRC patients. Altogether, our data uncover a protective role for VSIG4 LPMs in infectious and oncological diseases in the peritoneal cavity.