Introduction: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody–positive double-seronegative myasthenia gravis (DNMG). Methods: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. Results: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor–related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤.02). Antibody-positive patients’ maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤.005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody–positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. Discussion: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.