Antibodies to Ca channels in ALS patients IgG can be demonstrated to enhance Ca current and cause cell injury and death in a motoneuron cell line in vitro. To determine whether these antibodies can alter neuronal calcium homeostasis in vivo IgG fractions from six ALS patients were injected intraperitoneally into mice, and neurons assayed by ultrastructural techniques for calcium content. After 24 h, all six ALS IgG by (40 mg/animal) increased vesicle number in spinal motoneuron axon terminals, and in boutons synapsing on spinal motoneurons. Using the oxalate-pyroantimonate technique for calcium precipitation, these antibodies produced dose-dependent calcium increases either in axon terminal synaptic vesicles and mitochondria, or in rough endoplasmic reticulum, mitochondria, and Golgi complex of spinal motoneuron and frontal cortex pyramidal cells. ALS IgG was itself internalized and also induced neurofilament H phosphorylation. The observed changes in ultrastructure and calcium compartmentation were restricted to motoneurons; normal and disease control IgG, which did not possess antibodies enhancing calcium entry, did not exert similar effects. These data demonstrate that ALS IgG containing Ca-channel antibodies can alter calcium homeostasis of motoneurons in vivo.