Because of serious adverse effects, the Food and Drug Administration warns against using lopinavir in infants younger than 42 weeks postconception. However, there is an imperative for early treatment. We report on our use of LPV in 8 premature HIV-infected infants. The median age at initiation was 27 days. Trough values guided dosing. Five infants needed doses above 300 mg/m2. Although no adverse events were noted, lopinavir usage requires caution and careful monitoring.