Objectives: This study was designed to determine whether the complement (C) system may be involved in the febrile response to zymosan (Zym), a glycan derived from yeast cell walls. Methods: Cobra venom factor (CVF) at 100 U/animal or its vehicle, pyrogen-free saline (PFS), was injected intravenously (i.v.) into guinea pigs to deplete serum C. Eighteen hours later, a low or high dose of Zym or its vehicle, PFS, was administered i.v. or intraperitoneally (i.p.) to these animals. The core temperature (T<sub>c</sub>) was measured continuously by thermocouples. Serum C levels were determined by sheep erythrocyte hemolytic assay. Results: Zym at 1 mg/kg caused a 1°C T<sub>c</sub> rise that was not significantly affected by CVF pretreatment. However, CVF-induced hypocomplementation converted the T<sub>c</sub> fall (∼1.2°C) produced by 100 mg/kg of Zym i.p. into a 1°C T<sub>c</sub> rise. Similarly, CVF pretreatment did not affect the T<sub>c</sub> rise caused by 0.5 mg/kg of Zym i.v., but converted the T<sub>c</sub> fall induced by 25 mg/kg i.v. into a 1°C T<sub>c</sub> rise. A separate experiment showed that 25, but not 0.5 mg/kg of Zym i.v., decreased serum C by 34% in 15 min; C did not recover over the next 6 h. A second i.v. injection of 25 mg Zym/kg 210 min later, when the T<sub>c</sub> had recovered but the serum C had not, yielded a smaller and briefer T<sub>c</sub> fall. Conclusion: These results suggest that Zym is inherently pyrogenic, but this effect is manifested only when the dose of zymosan is too small to activate C or when C has been reduced by prior activation.