Abstract：Immune response is one of the critical factors of limiting implantable biomaterials application. In this study, two kinds of collagen membranes for bone regeneration were evaluated immunological response in vivo, hoping to lay foundations for clinical trials. At day 14 following subcutaneous implantation of the two membranes in BALB/c mice, spleen and lymph nodes showed no obvious swelling, and normal lymph nodes cells population as well as one-fold more splenic cells population than negative control (NC, no implant) was observed. Flow cytometry analysis demonstrated in mice with collagen membrane 1, splenic T lymphocytes percentage decreased by 13%, but no significant change was discovered in T lymphocyte subsets; collagen membrane 2 did not trigger apparent splenic cells composition alteration; the two membranes activated one-fold more B lymphocytes than NC. Enzyme linked immunosorbent assay indicated that one-fold higher IgG concentration than NC was detected in mice with collagen membrane 1 at day 14. Lymphocytes proliferation assay in vitro did not show significant difference from NC. H&E staining of local tissues exhibited slight cell infiltration around the two membranes. The two collagen membranes have engendered mild immune response and can be applied to clinical trials.