Background: The use of antiretroviral therapy has improved the quality of life and has increased the survival of HIV-infected individuals. However, the rapid rate of virus mutation and subsequent emergence of drug-resistant HIV variants threaten the longer-term efficacy of HIV treatment. The initial regimen provides the greatest chance for lasting suppression of viral load. Aims: Appropriate selection of the initial antiretroviral regimen is critical. The growing number of drug classes allows healthcare providers to individualize treatment regimens. Factors influencing the selection of first-line therapy include baseline viral load and CD4 count, drug pharmacokinetics, potency, tolerability, safety, resistance and salvageability. Characteristics likely to affect adherence, such as regimen complexity and pill burden, must also be considered, as poor adherence is the most common cause of treatment failure. Conclusion: The selection of the initial regimen requires consideration of several factors. Drugs from new classes as well as new drugs from existing classes with favorable resistance and side effect profiles are in various stages of development. Many of these drugs will enhance available options for initial therapy. (C) 2002 Elsevier Science B.V. All rights reserved.