Peritoneal macrophages from Fischer 344 rats were cytotoxic for mouse fibroblasts after in vitro phagocytosis of non-biodegradable group A streptococcal cell walls. In contrast, macrophages from Buffalo rats were not activated to cytotoxicity by bacterial cell walls. Activation to cytotoxicity was only achieved by the macrophages after an interval of at least 3 days in culture after ingestion of group A cell walls. If macrophages were cultured only 24 h after ingestion of cell walls, a cytostatic effect on target cells was observed. Phagocytosis of biodegradable group D streptococcal cell walls did not activate macrophages from either rat strain to become cytotoxic. No direct toxicity of cell walls for macrophages or mouse L-cells was observed. The cytotoxicity of Fischer 344 macrophages appears to require direct cell contact with target cells.