The mechanism of initiation of the second body temperature (Tb) rise of the typically biphasic lipopolysaccharide (LPS) fever is not known. This study was undertaken to test the hypothesis that the second Tb rise during fever may be initiated as a direct consequence of the elevated Tb of the first febrile rise. Experiments were conducted in conscious guinea pigs implanted with intraperitoneal thermodes, intravenous catheters, and intrahypothalamic thermocouples. Intraperitoneal cooling (IPC) was performed by perfusing water (22 degrees C) through the thermode under afebrile conditions during the first (0-40 min after pyrogen injection) or second (80-120 min) phase of the biphasic LPS (2 g/kg iv) fever or during a monophasic LPS (0.5 g/kg iv) fever. Throughout IPC, the rate of heat withdrawal was maintained at 11.6 +/- 1.2 mW/g. No IPC was performed in the corresponding controls. When started immediately after LPS administration at the higher dose, IPC completely blocked the first phase of the biphasic fever. This blockade was followed by a Tb rise, which, although similar to the rise in the second phase, might alternatively be interpreted as the delayed occurrence of the first phase previously suppressed by IPC. However, we excluded the later possibility by showing the absence of an overshoot in Tb restoration after IPC applied during the second phase of biphasic fever, during monophasic fever, or under afebrile conditions. We conclude, therefore, that the second Tb rise of biphasic LPS fever is not induced by the elevated Tb of the first febrile phase. The cause of the second peak of the characteristic biphasic febrile response to intravenous LPS remains speculative.