Abstract Background Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse drug reaction associated with human herpesvirus reactivation. However, the risk factors for viral reactivation and their impact on outcomes remain unclear.We aimed to explore the impact of viral reactivation on DRESS outcomes and potential risk factors for reactivation. Methods This was a retrospective cohort study in an academic medical center. Cases were validated in-hospital cases of DRESS from 2009 to 2017. Results Overall, 100 patients fulfilled the case criteria. Ninety-three patients had at least one viral marker tested. HHV6, EBV and CMV reactivation occurred in 24 out of 85 cases (28%), 15 out of 87 (17%) cases, and 18 out of 89 (20%) cases respectively. Viral reactivation cases were associated with higher 1-year mortality, dialysis initiation, recurrent flares of disease, and longer hospital stay (all p<0.05). Risk of inpatient mortality (OR, 5.8; 95% CI, 1.7-20.7; p<0.01) and 1-year mortality (OR, 10.0, 95% CI, 2.9-34.9; p<0.01) increased with multiple viral reactivations. Viral reactivation was independent of demographics, comorbidities, treatment or causative drug. Conclusion Human herpesviridae viral reactivation in DRESS, particularly multiple viral reactivations, is associated with poorer clinical outcomes.