Progressive systemic sclerosis (PSS) is a disease of unknown aetiology. The presence of various immunological abnormalities and clinical overlapping with diseases such as systemic lupus erythematous have led to the characterization of PSS as an autoimmune disease. Involvement of natural killer (NK) cells in the pathophysiology of progressive systemic sclerosis has been considered. Enhanced NK activity and normal ADCC activity was observed in an homogeneous group of 16 PSS patients with mild progression and a duration of disease > 7 years. Several factors indicate that the observed increase in NK activity could be due to a high number of circulating effector cells. Enumeration of the main effectors of NK activity by morphology and phenotype showed significantly augmented numbers of large granular lymphocytes (LGL) and CD16+ cells. Moreover, the spectrum of target sensitivity to PSS patient cells was unchanged when compared with controls indicating that enhancement may depend on an increase in the number of circulating NK cells rather than their intrinsic activation.