This study was to evaluate the cytotoxic effect in vitro and the tissue response within the rat peritoneal cavity to high copper amalgam and glass ionomer-silver cement, suggested for use as a retrograde endodontic filling material. In the cytotoxicity experiment, the radioactively ($^{51}Cr$) labeled L929 mouse fibroblasts were employed to determine the relative cytotoxicity of two experimental materials. Those materials were evaluated immediately after set and after one and seven days setting. In the tissue response experiment, two experimental materials were to evaluate mean peritoneal cellular count, differential cell count and the content of silver and copper in pooled packed cells and eluate samples taken by peritoneal lavage technique, and compared with surgical control after one day. two, four and six weeks of implantation. The results were as following: 1. High copper amalgam exhibited significant cytotoxicity immediately after set but showed no sign of toxicity after one day and seven days setting materials. 2. Glass ionomer-silver cement showed no sign of toxicity immediately after set and after one day and seven days setting. 3. High copper amalgam and glass ionomer-silver cement groups produce no significant difference in the mean peritoneal cell count when compared with the surgical control group after one day, two and four weeks of implantation. Surgical control group exhibited significantly a greater cell count when compared with the High copper amalgam group after six weeks. 4. High copper amalgam group increased significantly in the percentage macrophages after four and six weeks of implantation when compared with surgical control group. 5. The trace metal analysis involved an increased silver content in the elutes and an increased copper content in the packed cells of high copper amalgam group, and an increased silver content in the packed cells and elutes of glass ionomer-silver cement group.