The aim of the study was to investigate the effects of small intestinal submucosa (SIS) sponges, a natural biodegradable polymer scaffold, on the adhesion behavior and the proliferation of Schwann cells (SCs). SIS sponges were prepared by varying the contents of SIS powders (1%, 2%, and 3% SIS concentration) and SCs were seeded on the sponges and incubated to investigate the adhesion and proliferation of SCs. A series of analytical process was conducted to observe the water absorption rate of sponges and confirmed the proliferation and morphology of SCs by scanning electron microscopy (SEM), 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, reverse transcription polymerase chain reaction (RT-PCR), and histological evaluation. The best adhesion behavior and the proliferation of SCs were observed on the sponge with 2% powder content. Also, analysis of messenger ribonucleic acid (mRNA) expression using the neuron-specific enolase (NSE) and neurofilament protein (NF) nerve markers showed that SC gene expression was excellent in the 2% SIS sponge. In vivo hematoxylin and eosin (H&E) staining and immunofluorescence results showed that cells and tissue formed well in the pores of sponges with 2% and 3% SIS powder contents, compared with formation in the 1% SIS sponge. The SIS sponges provided an unsuitable habitat for the adhesion and proliferation of cells in that the pore size was small. In this study, the adhesion behavior and the proliferation could be changed depending on the pore size and SIS powder content in the sponges. Thus, an appropriate powder content of SIS should be used to prepare SIS sponge scaffolds.