Inclusion body myositis developed in two men, 36 and 48 years old with long-standing common variable immunodeficiency. Immunophenotypic analysis of the endomysial cells showed an increased number of natural killer (NK) cells (defined as CD57+, CD56+, CD3-, CD8-, CD68-) accounting for 8.5 to 9.5% of the total cells, compared with a mean of 1% in sporadic inclusion body myositis. The remaining cells were CD8+, macrophages, and CD4+ T cells. NK cells were positive for intercellular cell adhesion molecule-1 and invaded muscle fibers negative for major histocompatibility complex (MHC) class I. In contrast to ubiquitous endomysial expression of MHC class I antigen in sporadic inclusion body myositis, the MHC class I in common variable immunodeficiency and inclusion body myositis was absent or weakly expressed in only some of the muscle fibers surrounded by CD8+ cells. Enteroviral or retroviral RNA sequences were not amplified. Treatment with intravenous immunoglobulin improved strength in 1 patient whose repeated muscle biopsy specimen showed normal NK cells. We conclude that inclusion body myositis can develop in patients with common variable immunodeficiency. Common variable immunodeficiency with inclusion body myositis is an immune myopathy mediated by NK cells in a non-MHC class I-restricted cytotoxicity, and by CD8+ cells in an MHC class I-restricted process. This is the first description of an inflammatory myopathy in which NK cells participate in the myocytotoxic process.