Pathogenesis in aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorders (herein called NMO) involves complement-dependent cytotoxicity initiated by AQP4-IgG binding to astrocyte AQP4. We recently reported that rats lacking complement inhibitor protein CD59 were highly susceptible to development of NMO pathology in brain and spinal cord following direct AQP4-IgG administration (Yao and Verkman, Acta Neuropath Commun 2017, 5:15). Here, we report evidence that CD59 is responsible for protection of peripheral, AQP4-expressing tissues in seropositive NMO. Rats made seropositive by intraperitoneal injection of AQP4-IgG developed marked weakness by 24 h and died soon thereafter. Serum creatine phosphokinase at 24 h was >900-fold greater in seropositive CD59^−/− rats than in seropositive CD59^+/+ (or control) rats. AQP4-expressing cells in skeletal muscle and kidney, but not in stomach, of seropositive CD59^−/− rats showed injury with deposition of AQP4-IgG and activated complement C5b-9, and inflammation. Organ injury in seropositive CD59^−/− rats was prevented by a complement inhibitor. Significant pathological changes in seropositive CD59^−/− rats were not seen in optic nerve, spinal cord or brain, including circumventricular tissue. These results implicate a major protective role of CD59 outside of the central nervous system in seropositive NMO, and hence offer an explanation as to why peripheral, AQP4-expressing cells are largely unaffected in NMO.