Granular hydrogels have recently attracted the attention for diverse tissue engineering applications due to their versatility and modularity. Despite previous studies showing enhanced viability and metabolism of cells encapsulated in these hydrogels, the in vitro immune response and long-term fibrotic response of these scaffolds have not been well characterized. Here, bulk and granular hydrogels are studied based on synthetic zwitterionic (ZI) and natural polysaccharide hyaluronic acid (HA) made with mechanical fragmentation. In vitro, immunomodulatory studies show an increased stimulatory effect of HA granular hydrogels compared to bulk, while both bulk and granular ZI hydrogels do not induce an inflammatory response. Subcutaneous implantation in mice shows that both ZI and HA granular hydrogels resulted in less collagen capsule deposition around implants compared to bulk HA hydrogels 10 weeks after implantation. Moreover, the HA granular hydrogels are infiltrated by host cells, including macrophages and mature blood vessels, in a porosity-dependent manner. However, a large number of cells, including multinucleated giant cells as well as blood vessels, surround bulk and granular ZI hydrogels and are not able to infiltrate. Overall, this study provides new insights on the long-term stability and fibrotic response of granular hydrogels, paving the way for future studies and applications.