We assessed the incidence of paraproteins and autoantibodies in 44 patients (mean age, 65.3 ± 1.9 years) with normal-pressure glaucoma and 41 patients (mean age, 68.8 ± 1.8 years) with primary open-angle glaucoma. Serum monoclonal proteins occurred more often (P = .0047) in patients with normal-pressure glaucoma (eight of 44, 18%) than in control subjects with primary open-angle glaucoma (zero of 41, 0%). Autoantibodies to extractable nuclear antigens, most often Sjogren's syndrome A antigen (SSA[Ro]), were also found more frequently (P = .0022) in patients with normal-pressure glaucoma (13 of 44, 30%) than in control subjects (one of 41, 2%). Paraproteins and autoantibodies to extractable nuclear antigens generally occurred in different patients with an overall incidence of 20 of 44 (45%) patients with normal-pressure glaucoma. In contrast, no significant difference in the incidence of antinuclear antibodies existed between the groups. These findings suggest that humoral immune mechanisms may have a role in the pathogenesis of optic neuropathy in patients with normal-pressure glaucoma.