Objective Shuanghuanglian injection(SHL) frequently occurs anaphylactoid reactions. The main aim of the present study was to investigate that injected exogenous macromolecules are an important cause for anaphylactoid reactions using C48/80, a tool agent. Methods Component A (rich in macromolecules above 10 kDa) and component B (free of substances above 10 kDa) were prepaired from the original C48/80 or the original injection. The original, component A and component B from C48/80 or SHL were uesed for routine anaphylactoid test in rabbits and guinea pigs, and for pulmonary capillary permeability examination in rats. Results The original C48/80 contain more than 10% substances above 10 kDa, and SHL contained colored macromolecules. Component A from C48/80 or SHL caused a strong anaphylactoid reaction in guinea pigs by intravenous administration. Component A from C48/80 triggered mast cell degranulation while that from SHL did not. In addition, component A from C48/80 and SHL cuased a similarly strong passive cutaneous anaphylactoid (PCA) reaction, and also caused a strong pulmonary capillary permeability. The PCA reaction and permeability caused by component A both from C48/80 and SHL were largely prevented by cromolyn sodium. Nevertheless, component B containing substances below 10 kDa almost caused no anaphylactoid reactions; if happened, much weaker. Conclusion All the results suggested that injected macromolecular substances are one of the main factors responsible for anaphylactoid reactions caused both by C48/80 and SHL. The increase of vascular permeability participates the anaphylactoid reactions ignited by C48/80 and SHL.