The fixed-dose combination of emtricitabine (FTC) 200 mg and tenofovir disoproxil fumarate (TDF) 300 mg (Truvada(®)), administered orally once daily, is widely used as part of first-line regimens for the treatment of HIV-1 infection. Recently, once-daily administration of FTC/TDF was approved in the USA for pre-exposure prophylaxis in conjunction with safer sex practices to reduce the risk of sexually acquired HIV-1 in high-risk adults who are not infected. To date, results of four large, randomized, double-blind, placebo-controlled, multicentre trials with FTC/TDF as pre-exposure prophylaxis have been published. Three studies showed statistically significant reductions in the number of individuals with emergent HIV-1 infection when FTC/TDF was compared with placebo over the ≈1- to 2-year study periods. Efficacy (i.e. risk reduction relative to placebo) was 44 % in the iPrEx trial in men who have sex with men, 75 % in the Partners PrEP study in heterosexual HIV-1-serodiscordant couples and 62 % in the TDF2 trial in heterosexual men and women. The fourth study (FEM-PrEP) in heterosexual women did not show a statistically significant difference between FTC/TDF and placebo, although low adherence rates reported in this trial may have been a factor. No unexpected adverse events were reported in the trials. However, since pre-exposure prophylaxis involves long-term administration of drugs to healthy individuals, it is important to monitor the long-term safety of FTC/TDF (e.g. renal function, bone mineral density) in this setting. Other notable considerations include adherence, cost and the potential for development of drug resistance. Interim guidelines are available for prescribing FTC/TDF as pre-exposure prophylaxis. If used appropriately in selected high-risk individuals, pre-exposure prophylaxis with FTC/TDF represents an important additional strategy to reduce the spread of HIV-1 infection, which continues to be a significant global concern.