Reactivation of latent Epstein-Barr virus (EBV) and/or Cytomegalovirus (CMV) infection is a dreaded complication in immunocompromised patients receiving hematopoietic stem cell transplantation. Evidence is sparse if subclinical reactivation of viral infection may also be of clinical relevance in dermatological patients. We screened patients (n= 206) suffering from chronic skin diseases for subclinical reactivation of EBV and CMV infection. We found that immunocompromised patients with therapy-refractory chronic skin diseases showed higher rates of subclinical reactivation of CMV and EBV infection (6.7 % vs. 0 % for EBV and 16.7 % vs. 5.6% for CMV) and higher prevalence of virus specific DNA in skin tissue (30.8 % vs. 0% for EBV and 21.4% vs. 0% for CMV) as compared to non-immunocompromised patients with chronic skin diseases. T cells isolated from lesional skin exhibited up to 14-fold increased proliferation with production of Th1 and Th17 cytokines upon stimulation with viral proteins providing evidence for possible aggravation of the underlying skin diseases by viral infection. Improvement of skin lesions in patients with reactivation of CMV infection (n=4) was observed upon anti-viral treatment. Our data suggests that subclinical reactivation of EBV and/or CMV infection is an under-recognized condition in the dermatological patient population with chronic skin diseases.