With advancing age, a natural decline in cell-mediated immunity to varicella zoster virus (VZV) results in virus reactivation (herpes zoster) often complicated by VZV vasculopathy. Last year, we encountered elderly individuals presenting with visual symptoms, headache, elevated sedimentation rates and C-reactive protein, all features characteristic of giant cell arteritis (GCA). GCA is a serious disease in which temporal artery biopsy reveals granulomatous vascular inflammation diagnostic of disease. However, the temporal arteries of our patients were negative for GCA pathology, but contained VZV antigen, indicative of multifocal VZV vasculopathy. Importantly, our earlier published studies revealed no VZV in temporal arteries from patients with pathologically verified GCA, indicating that the current cases of multifocal VZV vasculopathy with temporal artery infection are distinct from GCA. Since most patients with clinically-suspect GCA have a negative temporal artery biopsy, it is likely that a significant subset of these patients have multifocal VZV vasculopathy with temporal artery infection. In fact, our examination of GCA-negative temporal artery biopsies revealed VZV antigen in 5 (21%) of 24 arteries, providing the definitive rationale for our hypothesis that a significant proportion of patients with clinically-suspect GCA have multifocal VZV vasculopathy with temporal artery infection, an eminently treatable disorder. Our findings may also help to explain why temporal artery biopsy of patients with clinically-suspect GCA is negative in >50% of patients. We have archived temporal arteries from 150 subjects pathologically negative for GCA and will analyze an additional 1464 temporal arteries obtained from our collaborators at 7 major university hospitals in the next 5 years (total of 1614 arteries). We will determine the frequency of VZV in temporal arteries in GCA negative subjects and identify the spectrum of clinical features, laboratory abnormalities and pathological changes in patients with VZV vasculopathy mimicking GCA. Proving that patients with clinical features and laboratory abnormalities suggestive of GCA are manifestations of multifocal VZV vasculopathy will significantly impact and change clinical practice. Patients presenting with symptoms of GCA may need treatment with both steroids and antiviral agents until a definitive diagnosis is made; otherwise, steroid treatment alone in patients with multifocal VZV vasculopathy may lead to blindness and stroke.