The objective of this study was to develop a 3D cell culture model of the human subcutaneous tissue, allowing the prediction of the immunogenicity of subcutaneously injected therapeutic proteins. Several hydrogels were evaluated as scaffolds to mimic the human subcutaneous tissue in vitro. Cytocompatibility of the hydrogels with the human myelomonocytic cell line (MUTZ-3) was investigated, as well as their influence on cellular phenotype changes. Elastic Young's moduli in compression of the hydrogels were measured by a texture analyser and compared to ex vivo human samples. MUTZ-3 cells were differentiated into dendritic cells before embedding in hydrogels. Agarose at various concentrations (0.5%, 0.35% and 0.25% w/v), Geltrex® matrix and HyStem™ scaffold (1% w/v) displayed a wide range of elastic Young's moduli from 560 kPa to 49 kPa, compared to the reference value of 23 kPa obtained for human tissue. With the exception of HyStem™, good cytocompatibility of hydrogels was shown at the concentrations tested. An optimal combination of MUTZ-3 cells with 0.25% agarose or Geltrex® is suggested.