Two antilipidemic compounds, clofibrate and procetofene, inhibited the replication of herpes simplex virus type 1 (HSV-1) in African green monkey kidney cells. Clofibrate, at a concentration of 400 ,umol/liter caused a 63% reduction (P < 0.001) in HSV-1 yield and at 100 pnol/liter caused a 62% reduction (P < 0.001) in plaque formation. Two stereoisomeric analogs of clofibric acid, (-)-and (+)-desmethyl clofibric acid, also caused a significant inhibition of HSV-1 replication.Procetofene at 5 ,Lmol/liter caused a 56% reduction (P < 0.001) in HSV-1 plaques and at 10 ,umol/liter caused a significant reduction (P < 0.001) in both viral yield (42 to 54%) and plaque formation (65%). Procetofene also inhibited the development of HSV-1 plaques. A concentration of 5 ,umol/liter resulted in a 26% reduction (P < 0.001) in plaque diameter. Because of their nonspecific inhibitory effect on the uptake of cellular macromolecular precursors for nucleic acid and protein biosynthesis, these antilipidemic compounds may exert their antiviral activity by affecting one or more key metabolic host cell pathways.