Dilated (congestive) cardiomyopathy is a disease of uncertain aetiology in which viral and immune factors are postulated to be of importance. Natural killer cells mediate natural resistance to viral infections and certain tumours. To evaluate natural killer (NK) activity in patients with cardiomyopathy, circulating peripheral blood mononuclear cells were obtained from 16 patients, from 54 normal blood donors, and from 14 patients with heart failure due to other causes (primarily coronary disease). NK activity was assessed as a lymphocyte to target cell ratio causing 50% killing (L/T50). L/T50 in normals was 17.2 +/- 11.4. A normal L/T50 distribution was also noted in heart failure controls (L/T50 = 19.6 +/- 9.9) and 8/16 cardiomyopathy patients (L/T50 = 17.5 +/- 9.5). NK activity was deficient (L/T50 greater than or equal to 50) in 8/16 patients with cardiomyopathy but in only 2/54 normals (p less than 0.001) and 0/14 heart failure controls (p less than 0.01). Of the several clinical and laboratory variables examined, only the frequency of the HLA-A3 tissue type was associated with NK deficiency. NK deficiency is an independent disease marker in about 50% of patients with cardiomyopathy and should be evaluated for a possible role in its pathogenesis.