Aqueous humor samples from nine patients with atypical necrotizing retinopathies of suspected viral origin, six with acute retinal necrosis syndrome (ARN), and 17 with active cytomegalovirus (CMV) retinitis underwent amplification for viral DNA of herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV), and human CMV. VZV DNA was detected in seven of the nine aqueous humor samples from patients with atypical necrotizing retinopathies of suspected viral origin and in four of the six samples from individuals with ARN; of the two other samples from patients with ARNS, no viral DNA was found in one, and both CMV DNA and HSV-1 DNA, but not VZV DNA, were detected in one (this patient presented with bilateral ARNS 2 months after being successfully treated for CMV retinitis). Thus, VZV is likely to be the main pathogen of atypical necrotizing herpetic retinopathies. DNA amplification may be used to establish an early, sensitive, and reliable diagnosis of any form of necrotizing retinopathy in 80% of cases, irrespective of viral etiology.