There are currently several suitable and different antiretroviral regimens to start highly active antiretroviral therapy (HAART), and many clinicians and patients prefer once-daily therapy. The efficacy and potency of efavirenz (EFV) has been established in many clinical trials and cohort studies; its pharmacokinetics, allowing for a convenient once-daily administration, make EFV one of the first agents to be included in once-daily regimens in naive patients. The two nucleoside reverse transcriptase inhibitors (NRTIs) accompanying the third drug have become the central skeleton, or the 'backbone' of the therapeutic scheme. Among the different NRTI pairs, a didanosine-lamivudine (3TC) or emtricitabine backbone for combination antiretroviral therapy may be a good option compared with any current NRTI-combinations due to its security, tolerance and once-daily dose. In this article, we review the advantages and drawbacks of didanosine-XTC-EFV as the initial regimen of HAART in HIV-infected patients.