Background Interferon (IFN) can inhibit human immunodeficiency virus type 1 (HIV-1) replication in vitro and in clinic.However, IFN therapy for HIV infection was limited by its moderate antiviral efficacy and its frequent adverse effects. In the present study we evaluated the anti-HIV efficacy of a novel synthesized superior interferon α (slFNα).Methods We performed in vitro experiments with HIV-1 IIB infected MT4 cells, and evaluated in vivo anti-HIV efficacy of slFNα in severe combined immunodeficient (SClD) mice reconstituted with human peripheral blood leukocytes (hu-PBL-SClD mice).Results We found that the 50% effective concentrations (EC5o) of slFNα against the replication of HIV-1 in MT4 cells was 0.06 ng/ml, representing stronger antiviral activity than interferon-α in vitro. In the hu-PBL-SCID mice, a dose-dependent protection pattern was observed: with 0.45 μg and 1.35 μg slFNα daily treatments, parts of SCID mice were protected from HIV infection, whereas 2.25 μg sIFNα daily treatments resulted in a terminally complete protection.Conclusions slFNα shows good anti-HIV activity both in vitro and in SCID mice, may be a promising anti-HIV agent deserving clinical investigation, especially considering the potential of IFN-α to inhibit HIV replication in patients infected with drug-resistant variants or co-infected with hepatitis C virus (HCV).