By studying fifty COVID-19 patients, researchers in France identified a unique signature – a combination of deficiency in a response of a particular interferon, as well as exacerbated inflammation – in the most critically ill. They propose this signature, which may be a hallmark of severe COVID-19, provides a rationale for therapeutic approaches that combine interferon supplementation with neutralization of inflammatory signaling. COVID-19 is characterized by distinct patterns of disease progression depending on the patient, which implies patients exhibit different immune responses to the SARS-Cov-2 virus. So far, studies suggest some 5-10% of patients progress to severe or critical disease. However, little is known about the immunological features involved in COVID-19 severity. To help to fill this gap, Jérome Hadjadj and colleagues analyzed immune cells of COVID-19 patients with symptoms ranging from mild to critical. The critical patients exhibited a distinctive dual signature involving a deficiency in responses of type I interferons, proteins that help fight viral infections, as well as exacerbated proinflammatory signaling. While recent work to investigate the role of interferon signaling in COVID-19 patients has shown that local interferon signaling may be important to mitigate disease progression, the results of Hadjadj et al. suggest broader production of interferons may in fact be beneficial. The work of these studies collectively reinforces a growing hypothesis that the location, timing, and duration of interferon exposure are critical parameters underlying the success of therapeutics for SARS-CoV-2 infections. Hadjadj et al. also suggest severely ill COVID-19 patients could be treated with a combined approach focused on interferon administration and adapted anti-inflammatory therapies, “a hypothesis worth cautious testing,” they say.