BACKGROUND Anifrolumab, a monoclonal antibody targeting the type 1 interferon (IFN-I) signaling pathway, holds promise as a therapeutic intervention for systemic lupus erythematosus (SLE). However, its use is associated with an increased risk of infections, particularly viral infections like herpes zoster (HZ). Results from the clinical trials on anifrolumab show yearly rates of upper respiratory tract infections of 34% and HZ of 6.1%. An increased frequency of other specific viral infections, including herpes simplex virus (HSV), was not reported. CASE REPORT Here, we present 2 cases of patients with SLE treated with anifrolumab, both experiencing severe adverse reactions in the form of disseminated herpesvirus infections, specifically disseminated HSV-2 and varicella zoster virus (VZV, HZ encephalitis). To the best of our knowledge, no previous reports of severe disseminated HSV-2 or HZ have been published in anifrolumab-treated patients. The patient in case 1 experienced a primary HSV-2 infection following anifrolumab treatment, potentially explaining the severity of the infection. The patient in case 2 had a history of previous HZ skin infections, which may have increased her risk of disseminated infection. Both patients recovered from the infections with minor sequelae, but they still require prophylactic antiviral treatment. These cases highlight the critical role of IFN-I immunity in protecting against herpesvirus infections. CONCLUSIONS Thorough risk assessment before anifrolumab initiation, considering the patient's viral infection history, vaccination status, and potential exposure risks, is essential. Administration of recombinant zoster vaccine before anifrolumab therapy may benefit susceptible individuals.