We measured the complement-dependent cytotoxic activity of serum in 60 patients with pernicious anemia. Canine gastric mucosal cells served as the indicator of cytotoxicity, which was expressed as a percentage of the maximal effect produced by a cytolytic agent (Triton X-100). Serum from patients with pernicious anemia showed a higher average activity (11.8 +/- 10.3 per cent, P less than 0.001) than serum from 29 patients with systemic lupus erythematosus (1.0 +/- 1.8 per cent), 10 with scleroderma (0.1 +/- 0.1 per cent), 10 with rheumatoid arthritis (0.6 +/- 0.6 per cent), 22 with multiple sclerosis (0.4 +/- 1.2 per cent), and 23 with chronic persistent hepatitis (0.03 +/- 0.1 per cent), and serum from 64 healthy persons (0.4 +/- 1.0 per cent). Serum from patients with pernicious anemia was not toxic to canine liver or kidney cells. Absorption with gastric mucosal cells and heat inactivation of complement abolished the cytotoxic reaction. The cytotoxic factor resided in the IgG fraction of immunoglobulin, and the amount of cytotoxicity was proportional to the IgG concentration. Cytotoxic activity correlated with the presence of parietal-cell-surface--reactive autoantibody demonstrated by immunofluorescence. We conclude that cytotoxic autoantibodies to parietal cells may contribute to the loss of such cells from the gastric mucosa of patients with pernicious anemia.