Binding of the Fc domain of Immunoglobulin G (IgG) to Fcγ receptors on leukocytes can initiate a series of signaling events resulting in antibody-dependent cell-mediated cytotoxicity (ADCC) and other important immune responses. Fc domains lacking glycosylation at N297 have greatly diminished Fcγ receptor binding and lack the ability to initiate a robust ADCC response. Earlier structural studies of Fc domains with either full length or truncated N297 glycans led to the proposal that these glycans can stabilize an “open” Fc conformation recognized by Fcγ receptors. We determined the structure of an E. coli expressed, aglycosylated human Fc domain at 3.1 Å resolution and observed significant disorder in the C′E loop, a region critical for Fcγ receptor binding, as well as a decrease in distance between the C_H2 domains relative to glycosylated Fc structures. However, comparison of the aglycosylated human Fc structure with enzymatically deglycosylated Fc structures revealed large differences in the relative orientations and distances between C_H2 domains. To provide a better appreciation of the physiologically relevant conformation of the Fc domain in solution, we determined Radii of Gyration (R_g) by small-angle X-ray scattering (SAXS) and found that the aglycosylated Fc displays a larger R_g than glycosylated Fc, suggesting a more open C_H2 orientation under these conditions. Moreover, the R_g of aglycosylated Fc was reduced by mutations at the C_H2–C_H3 interface (E382V/M428I), which confer highly selective binding to FcγRI and novel biological activities.