Objective: To compare the antipyretic benefit of acetaminophen or ibuprofen monotherapy with an alternating regimen of both drugs in young children aged 6 to 36 months. Design: Randomized, double-blind, parallel-group trial. Setting: Three primary pediatric community ambulatory centers in central Israel. Participants: A total of 464 children aged 6 to 36 months with fever. Intervention: Infants were assigned to receive either acetaminophen (12.5 mg/kg per dose every 6 hours) (n=154) or ibuprofen (5 mg/kg per dose every 8 hours) (n=155) or to receive alternating acetaminophen and ibuprofen (every 4 hours) (n=155) for 3 days after a loading dose. Main Outcome Measures: Temperature, stress score, amount of antipyretic received, total days that the infant or caregiver was absent from day care or work, respectively, at the 3-day time point, recurrence of fever, and number of emergency department visits. Results: The group given the alternating regimen was characterized by a lower mean temperature, more rapid reduction of fever, receiving less antipyretic medication, less stress, and less absenteeism from day care as compared with the other groups; all of the differences were statistically significant (P<.001). None of the regimens were associated with a significantly higher number of emergency department visits (P=.65) or serious long-term complications (P=.66). The drug used for initial loading had no effect on outcome in any of the groups. Conclusions: An alternating treatment regimen of acetaminophen (12.5 mg/kg per dose) and ibuprofen (5 mg/kg per dose) every 4 hours for 3 days, regardless of the initial loading medication, is more effective than monotherapy in lowering fever in infants and children.