The importance of cell-mediated immunity in cat-scratch disease (CSD) is suggested by the positive skin test reactions and granulomatous histopathology noted in patients with this disease. However, an earlier investigation found that lymphocytes from patients with CSD and control subjects were equally unresponsive in vitro to cat-scratch antigen. In contrast, we found that 16 patients with CSD had significantly increased lymphocyte transformation responses to cat-scratch antigen when patients were compared to control subjects. This cell-mediated immune response may be directed against nonviable bacteria in the involved lymph nodes and may be the major mechanism responsible for the granulomatous reaction and clinical features of CSD.