Selenoprotein K (Sel K) is an endoplasmic reticulum (ER) transmembrane protein that we have recently shown to play a role in calcium-dependent immune cell activation. Sel K-knockout mice exhibit deficient calcium flux in immune cells and impaired immune responses. In this study, we demonstrated that Sel K deletion resulted in decreased FcγR-mediated phagocytosis in mouse bone marrow derived macrophages (BMDM) compared to WT controls. To engage FcγR on BMDM, immune complexes (IC) were added comprised of either IgG-opsonized BSA (low avidity) or IgG-opsonized, BSA-coated beads (high avidity). Both types of IC induced Ca2+-dependent phosphorylation of ERK, but this was significantly decreased in Sel K-/- BMDM compared to controls. Nitric oxide (NO) was only induced with high avidity IC and was significantly decreased in Sel K-/- BMDM. PGE2, IL-6, and TNFα were induced by high avidity IC, but not low avidity IC, and were significantly reduced in Sel K-/- BMDM. Phagocytosis of high avidity IC produced lower oxidative burst in Sel K-/- BMDM. Consistent with this reduced oxidative burst, there was reduced destruction of IgG-opsonized West Nile virus in the phagolyzosome of Sel K-/- BMDM compared to controls. Overall, these results suggest that Sel K plays a role in FcγR-mediated signaling and effector functions of macrophages, and high avidity IC are required to induce maximal effects.