The importance of combination antiretroviral therapy in HIV-infection has been well established. However, many available agents suffer shortcomings that limit their clinical value, including adverse effects, difficult dosing requirements and rapid development of resistance. Lopinavir/ritonavir (Kaletra) is a member of the protease inhibitor class, specifically designed to address some of these deficits. The drug is a coformulation of lopinavir with low-dose ritonavir, exploiting a favourable drug-drug interaction between the two that yields sustained increases in plasma levels of lopinavir. In large-scale clinical trials, lopinavir/ritonavir has demonstrated superior therapeutic efficacy when compared with other protease inhibitors. It exerts potent antiviral activity in both treatment-naive and experienced patients with an acceptable incidence of adverse effects. De novo development of resistance has not been described in large clinical trials with patients naive to antiretroviral therapy. Lopinavir/ritonavir has recently been approved for once-daily dosing in antiretroviral-naive patients.