Impaired type I interferons (IFNs) production or signaling have been associated with severe COVID-19, further promoting the evaluation of recombinant type I IFNs as therapeutics against SARS-CoV-2 infection . In the Syrian hamster model, we show that intranasal administration of IFN- starting one day pre-infection or one day post-infection limited weight loss and decreased viral lung titers . By contrast, intranasal administration of IFN- starting at the onset of symptoms three days post-infection had no impact on the clinical course of SARS-CoV-2 infection . Our results provide evidence that early type I IFN treatments are beneficial, while late interventions are ineffective, although not associated with signs of enhanced disease . One Sentence SummaryThe timing of type I interferon treatment is a critical determinant of its efficacy against SARS-CoV-2 infection.