Adherence to highly active antiretroviral therapy (HAART) plays a critical role in the effectiveness of HIV treatment. Nevertheless, the complexity of regimens and frequent side effects make HAART extraordinarily difficult to take, and many HIV-infected persons fail to adhere. The current study offers an overview of the relationship between adherence and antiretroviral treatment-related variables. As for other chronic diseases, medication regimen complexity also has an impact on adherence in the management of HIV infection. In particular, the authors discuss the effect of pill burden, dosing frequency, dietary instructions, number and type of different medications prescribed, short- and long-term side effects, convenience, and ability to incorporate the treatment regimen into a daily routine. Medication side effects are common in HAART-treated persons and are associated with concurrent and future nonadherence. Simplification of regimens, adjustment of the drug schedule to the patient's specific lifestyle, and anticipation and self-management of side effects are treatment-based strategies to optimize HAART adherence and ensure the most effective, convenient, safe, and well-tolerated antiretroviral treatment.