The HIV-1 exterior envelope glycoprotein gp120 binds receptor (CD4) and co-receptors (CCR5/CXCR4) and is a major target for neutralizing antibodies. The two functionally conserved regions of gp120 involved in receptor binding are conformational in nature. It is likely that the elicitation of neutralizing antibodies to these targets will benefit by presentation of these sites to the humoral immune system under physiologic conditions. Initially, we investigated the ability of the molecular adjuvant C3d to enhance antibody responses to variant gp120 glycoproteins in phosphate-buffered saline (PBS). We utilized a gp120 variant glycoprotein deleted of N- and C-terminal sequences (gp120DeltaC1/C5) originally designed to eliminate immunodominant, non-neutralizing epitopes and characterized this protein when fused to two C3d elements (gp120DeltaC1/C5(C3d)(2)). In PBS, the gp120DeltaC1/C5(C3d)(2) proteins are able to elicit gp120 binding antibodies more efficiently than gp120 lacking C3d moieties. We then asked if we could observe C3d-enhanced immunogenicity of gp120 in the presence of the classical oil-in-water adjuvant, Ribi. In the presence of the Ribi, which contains the TLR-4 agonist monophospholipid A (MPL), antibodies elicited by the gp120DeltaC1/C5(C3d)(2) were of higher titer than those elicited by the identical protein in PBS. To determine if the elicited secondary response was due to a synergy between the C3d repeats and the Ribi, we then inoculated gp120DeltaC1/C5 protein in Ribi and observed that similar titers of anti-gp120 antibodies were elicited in comparison to the gp120DeltaC1/C5(C3d)(2) protein also inoculated in Ribi adjuvant. In Ribi, there was a small but consistent increase in gp120-specific antibody titer of a gp120DeltaC1/C5(C3d)(2) prime followed by two gp120DeltaC1/C5 boosts compared to three inoculations of either the gp120DeltaC1/C5 proteins or the gp120DeltaC1/C5(C3d)(2) proteins alone. We conclude that the molecular adjuvant C3d demonstrates utility in conditions where physiologic presentation of native protein structures is desired, but may have less benefit in the context of a relatively potent protein adjuvant such as Ribi.