Fatal meningoencephalitis caused by equine herpesvirus-1 (EHV-1) was diagnosed in a reticulated giraffe (Giraffa camelopardalis reticulate). The giraffe died following a history of stumbling, incoordination, and abdominal pain. Gross examination of the brain revealed asymmetric edema and red-brown discoloration, predominantly within the telencephalon. Microscopically, there was perivascular lymphohistiocytic cuffing, multifocal gliosis, and neuronal necrosis in the cerebrum. Necrotic neurons contained acidophilic intranuclear inclusions. EHV-1 was isolated from the brain of the giraffe, and polymerase chain reaction was positive on sections of the brain. Immunohistochemistry using an EHV-1–specific antibody identified positive staining in neurons, astrocytes, and endothelial cells. The giraffe had been housed with a group of zebras that were serologically positive for EHV-1 and suspected as the source of infection. This raises concerns for cross-species transmission of EHV-1 when housing equids together with other species in zoologic collections.