Lymphocyte proliferative responses to phytohemagglutinin, pokeweed mitogen, and herpesvirus (herpes simplex virus and infectious bovine rhinotracheitis virus) antigens were evaluated in the presence of various concentrations of the anti-herpesvirus drugs, methylmethoxydeoxyuridine (OCH3CH2UdR), cytosine arabinoside was inhibitory at 25 mug/ml and cytosine arabinoside was inhibitory OCH3CH2UdR per ml, lymphocyte proliferative responses were unaffected and were not abolished even by concentrations of 2,500 mug/ml. In contrast, adenine arabinocide was inhibitory at 25 mug/ml and cytosine was inhibitory at 5 mug/ml. Both direct and antibody-dependent lymphocyte cytotoxicity of herpesvirus-infected target cells were highly resistant to OCH3CH2UdR; concentrations of 1,000 mug/ml were only marginally inhibitory. The anti-herpesvirus activity of all three drugs is similar (0.5 to 8 mug/ml) (L.A. Babiuk, B. Meldrum, V.S. Gupta, and B. T. Rouse, submitted for publication). The drug OCH3CH2UdR should be given a careful, well-controlled evaluation of its effectiveness in the treatment of herpes simplex infections in animals, perhaps including humans, since our results using in vitro models show that cellular responses important for recovery from herpesvirus infections are unaffected by doses far in excess of those found be be antiviral.