Efavirenz (EFV) is a non-nucleoside widely used as first-line therapy for HIV-1 infection. Most of the research available on EFV comes from trials performed in industrialized countries and only a few studies have evaluated EFV in resource-limited settings (RLSs). In this article, we present a systematic review of the available randomized-controlled trials performed in RLSs that have compared EFV with other antiretrovirals, such as nevirapine and protease inhibitors. The data derived from these studies show that both EFV and nevirapine are adequate first-line therapy options for HIV-1 infection in RLSs, even in patients with concomitant tuberculosis. However, EFV may show a slight benefit in terms of toxicity and adverse events. By contrast, the data comparing EFV versus protease inhibitors is contradictory and further studies may be required to elucidate these discrepancies.