To investigate the nature of the inflammatory response in facioscapulohumeral muscular dystrophy (FSHD), we analyzed mononuclear cells in muscle sections obtained from 18 FSHD patients and 8 controls. Monoclonal antibodies reactive for T cells, T cell subsets, B cells, and NK cells were used for cell typing. Macrophages were identified by acid phosphatase reaction. The localization of perforin, granzyme A, MHC-I and -II, dystrophin, and alpha-actinin antigens was also examined. We found that all FSHD patients, both familiar and sporadic cases, had greater amounts of mononuclear cellular infiltrates in muscle than controls, in whose specimens only few extra vascular mononuclear cells were counted. Seventy-two percent (13 of 18) of the patients had more than 50 inflammatory mononuclear cells per 1000 muscle fibers, and 33% (6 of 18) patients had numerous inflammatory cells exceeding 600 per 1000 muscle fibers (1835 +/- 482 SE). Nonnecrotic fibers invaded by mononuclear cells with either T8+, perforin+, or granzyme A+ were not observed in FSHD, while a few degenerating fibers were superficially invaded by T cells and macrophages. Occasional T cells were observed moving through the blood vessel wall. The increased number of necrotic fibers was paralleled by an increased number of inflammatory cells (r = 0.783, P = 0.0001). Genetic analysis, using the probes p13E-11, pFR-1, D4S139, and D4S163, was done in 6 patients (3 familiar, 3 sporadic) who had numerous inflammatory infiltrates. These 6 patients had small (< 28 kb) EcoRI fragments associated with the disease, and the disease was linked to 4q35. These results suggest that, in chromosome 4-linked FSHD: (1) inflammatory changes in muscle are a common histological feature; (2) mononuclear cellular infiltrates may enhance muscle fiber damage; but (3) T-cell-mediated cytotoxicity directed against muscle fibers is unlikely. We speculate that the immune effector mechanism in FSHD is different from that in previously reported inflammatory myopathies and Duchenne muscular dystrophy.