Previous morphological immunoenzymatic studies with organelle-specific antibodies have disclosed an apparent fragmentation of the Golgi apparatus in large numbers of motor neurons in 12 cases of sporadic, non-Guamanian amyotrophic lateral sclerosis (ALS) in three cases of other types of motor neuron disease and in one case of a mitochondrial myopathy with cytochrome c oxidase deficiency. Motor neurons with fragmented Golgi apparatus were moderately atrophic; in these cells, discrete immunostained elements of the organelle were twice as many as in normal neurons, and the size of each Golgi element and the percentage of the cytoplasmic area occupied by the Golgi apparatus were reduced (Am J Pathol 1992, 140: 731-737). In this report we have confirmed the fragmentation of the organelle of motor neurons in the spinal cord in six sporadic cases of Guamanian ALS. In four of the six cases the clinical course was 1 to 2 years. The percentages of motor neurons with fragmented Golgi apparatus varied from 38 to 92. Motor neurons from three additional cases of Guamanian ALS of clinical duration from 5 to 7 years did not show fragmentation of the Golgi apparatus. In two cases of Guamanian ALS and in one non-Guamanian ALS, all neurons with ubiquitin-positive skein-like or granular inclusions believed to be pathognomonic for ALS had fragmented Golgi apparatus. To examine whether the fragmentation of the Golgi apparatus results from reactions to either neuronal deafferentation or to lesions of proximal axons, we conducted two experimental studies. In the first study, we examined in cats the Golgi apparatus of deafferented neurons of the dorsal lateral geniculate nucleus. In the second study, we examined the Golgi apparatus of motor neurons in the spinal cord of rats with proximal axonopathy induced by beta,beta'-iminodipropionitrile. In these two experiments, the neuronal Golgi apparatus studied by immunoenzymatic techniques and morphometry, was not fragmented. Taken together, the results of these studies strongly suggest that the fragmentation of the Golgi apparatus of motor neurons in ALS represents an important and perhaps early change of the organelle that may be involved in the pathogenesis of ALS. The fragmentation of the Golgi apparatus of motor neurons is a fairly specific and easily recognizable marker of ALS and may be used together with other criteria for comparisons between the human disease and proposed animal models of the disorder.