Increasing interest in using soy biomaterials for tissue engineering applications has prompted investigation into the in vivo biocompatibility of soy implants. In this study, the biocompatibility of soy protein scaffolds fabricated using freeze-drying and 3-D printing was assessed using a subcutaneous implant model in BALB/c mice. The main objectives of this study were: (1) to compare soy protein with bovine collagen, a well-characterized natural protein implant, by implanting scaffolds of the same protein weight, and (2) to observe the effects of soy scaffold microstructure and amount of protein loading, which also alters the degradation properties, on the acute and humoral immune responses towards soy. Results showed that freeze-dried soy scaffolds fully degraded after 14 days, whereas collagen scaffolds (of the same protein weight) remained intact for 56 days. Furthermore, Masson’s trichrome staining showed little evidence of damage or fibrosis at the soy implant site. Scaffolds of higher soy protein content, however, were still present after 56 days. H&E staining revealed that macrophage infiltration was hindered in the denser bioplotted soy scaffolds, causing slower degradation. Analysis of soy-specific antibodies in mouse serum after implantation revealed levels of IgG1 that correlated with higher scaffold weight and protein density. However, no soy-specific IgE was detected, indicating the absence of an allergic response to the soy implants. These results demonstrate that soy protein could be an acceptable biocompatible implant for tissue regeneration, and that scaffold porosity, soy protein density and scaffold degradation rate significantly affect the acute and humoral immune response.