Durable and sustained suppression of HIV replication can be achieved as demonstrated in several recent clinical trials of antiretroviral (ARV) regimens. However, the efficacy demonstrated in the experimental setting does not always translate to effectiveness in the clinical setting. The frequency and number of medications (conventionally referred to as the pill count) contribute to regimen effectiveness. However, clinicians and HIV-infected patients recognise that there are several other characteristics of an ARV regimen that are equally important contributors to its effectiveness. Potency and durability, the potential for drug-drug interactions, and the occurrence of adverse events also contribute to the effectiveness and complexity of a drug regimen. A comprehensive consideration of factors associated with efficacy will optimise the translation to effectiveness for the individual infected with HIV.