Emergence of a multiply drug resistant Enterobacter cloacae during a seven-week period in 1980 caused amikacin to become the aminoglycoside of choice in the initial management of suspected sepsis in a neonatal intensive care unit. Recommended doses (7.5-10 mg/kg loading; 15 mg/kg in two divided doses IV) were given to 5 infants ≤ 1,000 gm and to 13 larger babies. Trough levels 11.5 hours after a dose were 16.6 ± 11.9 μg/ml in infants ≤ 1,000 gm and 6.5 ± 4.3 μg/ml in the larger infants (P<0.02). Peak levels one hour postinfusion exceeded 40 μg/ml in 3 of 5 ≤ 1,000-gm babies and 4 of 12 > 1,000-gm infants (P = NS). Overall, 7 of 10 peak and/or trough levels in ≤ 1,000-gm infants were in the range considered toxic in adults, versus 7 of 24 in larger babies (P = 0.03). These data show that surprisingly excessive blood levels of amikacin are likely in infants ≤ 1,000 gm and may also occur in larger infants using currently recommended dosage schedules. These unexpected finding emphasize the need to monitor drug levels and individualize therapy in very low birthweight infants.