Background.Several dosing schedules for gentamicin have been recommended for very low birth weight infants during the early neonatal period. We conducted a prospective, randomized, controlled trial to compare efficacy and pharmacokinetics of two dosing schedules in preterm neonates.Methods.Fifty-eight very low birth weight infants (600 to 1500 g), prescribed gentamicin for treatment of suspected sepsis during the first week after birth, were randomized to receive either the new dosing schedule [every 48 h (q48h)] or the existing dosing schedule [every 24 h (q24h)]. Infants in the “q48h” group received gentamicin at 5.0 or 4.5 mg/kg/dose q48h depending on weight group and infants in the “q24h” group received 2.5 or 3.0 mg/kg/dose q24h. Peak and trough serum gentamicin concentrations were monitored.Results.Peak serum gentamicin concentrations after the first dose were significantly higher in the q48h infants than in q24h infants (8.19 ± 1.3vs.6.04 ± 2.2,P= 0.00001). Ninety percent of all peak serum gentamicin concentrations in the q48h group were in a higher therapeutic range of 6 to 12 &mgr;g/ml as compared with 55% of q24h (P= 0.0005). None of the q48h infants had subtherapeutic serum gentamicin concentrations immediately after administration of the first dose as compared with 36% of q24h infants (P< 0.005). Eighteen percent of q24h infants continued to have peak serum gentamicin concentrations in subtherapeutic range even after the third dose at 48 h. Trough serum gentamicin concentrations were significantly lower in q48h infants than in q24h infants. However, 9 of 30 (30%) q48h infants had trough serum gentamicin concentrations of ≤0.5 &mgr;g/ml before the dose at 48 h and 4 of the 9 had serum gentamicin concentrations of <1 &mgr;g/ml at 24 h after the first dose.Conclusions.The q48h dosing schedule of gentamicin given to very low birth weight infants during the first week after birth achieved therapeutic serum gentamicin concentrations and potentially higher peak to MIC ratios for microorganisms in all infants. However, nearly one-third of the infants had extremely low serum gentamicin concentrations before the next dose. A dosing interval of 36 h might be optimal for bactericidal activity and avoid bacterial growth during prolonged periods of extremely low serum gentamicin concentrations; this dosing interval warrants study.