It is generally accepted that fever is associated with tachycardia and that the relationship, of an approximate increase of 10 beats/minute per °Celsius rise in temperature, is particularly pronounced in infants. It would be useful to determine how closely pulse and fever are associated during pharmacological temperature reduction, and whether it is influenced by the infectious status of the infant. Infants with fever presenting to the pediatric emergency department were prospectively enrolled in a study to determine temperature, heart rate, and the activity at initial assessment and 1 hour after antipyretic administration. Patients were also grouped into those with and without signs of serious bacterial infection for analysis. During pharmacological antipyresis, the relationship between pulse and fever deviated from the accepted norm, established during the febrile state: there was an average pulse rate reduction of 21.1 beats/minute/°Celsius decrement in fever (P = 0.0027; 95% CI, 14.05–28.15). Pulse reduction/°Celsius may also differ in infants with suspected serious bacterial infection. Our findings suggest caution in ascribing pulse changes to fever alone, especially in sick looking infants, and that this is especially true after the administration of antipyretics, which could be related to the mechanism of action of antipyretic drugs. Further research is needed to ascertain the clinical utility and importance of our observations.