Experimental herpes simplex virus type 1 (HSV-1) labyrinthitis provides a model of idiopathic sudden sensorineural hearing loss (ISSHL). Corticosteroids improve the prognosis for hearing recovery in ISSHL, but the effects of acyclovir are unknown. To establish the therapeutic efficacy of acyclovir (Zovirax) and prednisolone in experimental HSV-1 viral labyrinthitis, we induced HSV-1 labyrinthitis in 12 guinea pigs. Three animals received no treatment, 3 received prednisolone, 3 received acyclovir, and 3 received both. Four other animals served as controls, receiving culture medium only. Hearing, HSV-1 antibody titers, and cochlear damage were evaluated. The HSV-1 labyrinthitis caused hearing loss within 24 hours. Combination treatment consisting of prednisolone and acyclovir resulted in earlier hearing recovery and less extensive cochlear destruction compared to prednisolone or acyclovir as a monotherapy. The beneficial effect of this treatment modality remains to be demonstrated in ISSHL.