The antibody response to Herpesvirus saimiri (HSV)-induced membrane antigens (MA) was followed in HSV-infected owl monkeys using the membrane immunofluorescence (MF) and antibody-dependent lymphocyte cytotoxicity (ADLC) assays. These responses were correlated with the loss of T-cell responsiveness to general mitogens. Antibody titers to MA as determined by ADLC but not MF increased to remarkably high titers in those monkeys that developed malignant disease following virus infection, while remaining at relatively low and constant levels in those monkeys that developed a chronic virus infection in the absence of malignant disease. This disease-related antibody response pattern was paralleled by the loss of T-cell function in diseased animals. The development of leukemia in HVS-infected owl monkeys did not suppress the ability of peripheral blood lymphocytes to act as effector cells in the ADLC assay. The relationship of these immune response patterns to the development of malignant disease in this system is discussed.