Herpes simplex virus type 1 (HSV-1) uses a variety of mechanisms to avoid innate and adaptive host immune responses. Glycoproteins E (gE) and I (gI) form a viral Fc receptor that binds anti-HSV IgG molecules that have bound by their Fab domains to viral antigens on infected cell or virion surfaces. In this way gE/gI protect against Fc-mediated immune responses such as complement-enhanced antibody-dependent neutralization, phagocytosis, and antibody-dependent cellular cytotoxicity. Galectin-3, a carbohydrate-binding protein that is a monocyte, macrophage, and neutrophil chemoattractant, was identified by mass spectrometry from an anti-gI affinity column. We determined that galectin-3 did not specifically bind gI, but rather that HSV-1 infection increased binding of galectin-3 to carbohydrate residues on IgG in the affinity column. This conclusion was based upon the following observations: (1) galectin-3 from gInull infected cells bound anti-gI IgG; (2) galectin-3 from wildtype HSV-1 infected cells bound nonimmune IgG; (3) more galectin-3 from infected than uninfected cells bound IgG; and (4) binding to IgG was blocked by lactose, a competitive inhibitor of galectin-3 carbohydrate-binding. We also demonstrated that HSV-1 infection increases galectin-3 secretion. We propose that galectin-3 contributes to the early innate immune response of human cells to HSV-1 infection. The complement system plays an important role in the innate immune response to many pathogens. HSV-1 glycoprotein C (gC) interacts with complement component C3b and has an N-terminal domain that prevents interactions of properdin and CS with C3b. gC-1 inhibits complement activation and protects HSV-1 virions from complement-mediated neutralization and infected cells from complement-mediated lysis. Immune evasion of complement has previously been shown to increase virulence by 50-100-fold. We evaluated the early impact of immune evasion of complement and found that both the C3b-binding and N-terminal domains of gC-1 protected against complement-mediated neutralization of HSV-1. Using a mouse flank model of HSV-1 infection, we demonstrated that immune evasion of complement increased inoculation site titers at 1 day post-infection. We propose that by increasing inoculation site viral titers, immune evasion of complement allows increased spread of HSV-1 into the nervous system, the site of viral latency. In studies to evaluate this hypothesis, we detected a previously undiagnosed complement-independent non-gC defect in our panel of gC mutant viruses that reduced dorsal root ganglia titers and zosteriform site disease severity in vivo. Since our goal was to focus on gC-1, we attempted to generate a new panel of gC mutant viruses using a bacterial artificial chromosome (BAC) containing the full length genome of HSV-1 strain 17. We identified a previously undiagnosed frame shift mutation in the gC coding sequence that prevents gC expression by HSV-1 strain 17 BAC-derived viruses. A new panel of gC mutant viruses will be required to confirm the early impact of immune evasion of complement on virulence in vivo.