The role of lymphocytes in the pathogenesis of amiodarone-induced lung disease is controversial. Increases in the percentages of lymphocytes in bronchoalveolar fluid of both patients and animals with amiodarone pulmonary toxicity have been reported. To assess whether these lymphocytes are functionally activated, we measured natural killer cell activity in the lungs and blood of rats with amiodarone-induced pulmonary toxicity. Amiodarone treated rats exhibited pathologic evidence of amiodarone-induced lung disease after one week of treatment and this injury was sustained and more extensive during the remainder of the study period. Control rats had histologically normal lungs. Blood NK activity was equally present in both amiodarone-treated and control groups and was not significantly different over the course of the study (16 +/- 3 percent and 13 +/- 2 percent, respectively; p > 0.05). Thus, NK cells were activated only in the lungs of rats treated with amiodarone, suggesting a local immune response in the lung. These data support the concept that lymphocytes play an important role in the pathogenesis of amiodarone-induced lung disease.