We studied the immunologic correlates of disease activity and differences among subgroups of patients with idiopathic inflammatory myopathy by analysing phenotypic and activation marker expression on peripheral blood mononuclear cells (PBMC). Compared with controls, myositis patients with clinically active disease (n = 51) had significantly lower proportions of CD8+ cells and higher proportions of PBMC that expressed DR, CD3- DR, CD14- DR, interleukin-2 receptors, and the late T cell activation markers CD26 and TLiSA1. TLiSA1 expression, a marker for cytotoxic differentiation, correlated significantly with both clinical activity indices and serum levels of muscle-associated enzymes. In serial studies of seven patients, the proportion of PBMC expressing MHC class II antigen and late T cell activation markers decreased as myositis disease activity decreased, independent of type of therapy. Among the clinical subgroups, polymyositis (n = 21) and inclusion body myositis (n = 11) were virtually indistinguishable; dermatomyositis patients (n = 19) showed decreased proportions of CD3+DR+ and TLiSA1+ cells, and increased proportions of CD20+ and CD20+DR+ cells compared with the other two groups. Patients with autoantibodies to histidyl-tRNA synthetase (Jo-1 antigen, n = 11) had significantly lower proportions of CD3+ and CD4+ cells, lower CD4/CD8 ratios, and higher proportions of CD+ cells expressing CD20, compared with patients without anti-Jo-1 antibodies. These findings support the concept that activated lymphocytes, especially cells undergoing anamnestic responses and cytotoxic differentiation, are important in the pathogenesis of idiopathic myositis. Moreover, taken together with other studies, these data suggest that groups of patients segregated by clinical or autoantibody status have different mechanisms of systemic immune activation and immunopathology.