To characterize the giant cells in tuberous sclerosis, we examined immunoreactivity for nestin, vimentin, microtubule-associated protein 1B (MAP1B), MAP2, neurofilament, and glial fibrillary acidic protein (GFAP) in cortical tubers detected in brain specimens from 6 patients with tuberous sclerosis who had undergone surgical resection for treatment of intractable epilepsy. Giant cells with a neuronal appearance, "neuron-like giant cells," had a round centrally-placed nucleus with a single, prominent nucleolus, and Nissl substance was commonly present in cortex. These neuron-like giant cells demonstrated consistently strong immunoreactivity for neurofilament and MAP1B and occasional immunopositivity for nestin and vimentin and were rarely positive for GFAP. "Indeterminate giant cells," characterized by abundant cytoplasm, an absence of Nissl substance, and one or more eccentric nuclei, demonstrated consistent immunoreactivity for nestin, vimentin, and MAP1B and were rarely positive for neurofilament, but more than half displayed immunoreactivity for GFAP. These observations suggest that the indeterminate giant cells exhibit limited neuronal and inconsistent astroglial characteristics, implying aberrant cellular differentiation in tuberous sclerosis.