In clinical and experimental studies, silicone gel has been assumed to cause immune alterations that may be related to macrophage activation of silicone implants. However, it has not been proven that the immunotoxicities are caused by the direct contact of macrophages and silicone gel because there has not been an adequate experimental model. In the present study, silicone gel was loaded directly onto Petri dishes and was distributed uniformly to the bottom by centrifugation. Peritoneal macrophages and splenic lymphocytes were cultured either on the silicone-coated plates or on the conventional, normal plates, and their functions were compared with each other. The experiments were repeated three times. The cytotoxic activities of peritoneal macrophages on cancer cells were markedly augmented by cultivation on silicone gel, and the primary T-dependent immunoglobulin M response in which macrophages participated as antigen presenting cells was also enhanced by incubation on silicone gel. However, macrophage-unrelated functions mediated by B and T lymphocytes were not affected by the silicone gel treatment. It was proven that the direct contact of macrophages with silicone gel was a primary cause of acute immune activation that was related to foreign body reaction. In addition, the present in vitro model exhibited similar silicone-induced immunotoxicities in previous animal and clinical studies.