Epilepsy is associated with significant neurological morbidity, including learning disabilities, motor deficits, and behavioral problems. Although the causes of neurological dysfunction in epilepsy are multifactorial, accumulating evidence indicates that seizures in themselves may directly cause brain injury. Although it is clear that seizures can result in neuronal death, it is likely that under some circumstances seizures can induce more subtle functional or structural alterations in neurons. We induced focal neocortical seizures with 4-aminopyridine in transgenic mice expressing green fluorescent protein in cortical neurons and sequentially imaged individual dendrites in living animals with two-photon laser-scanning microscopy to determine whether these seizures caused acute alterations in dendritic spine morphology. No dendritic alterations were observed in anesthetized animals during electrographic seizures over a 3-hour period. Similarly, in unanesthetized mice, low-stage, clinical electrographic seizures had minimal effect on dendritic spines. More severe, high-stage seizures in unanesthetized mice were associated with a moderate loss of spines and dendritic swelling, but this effect may have been contingent on a synergistic action of phototoxicity from the imaging method itself. Overall, our results suggest that most neocortical seizures have minimal acute effects on dendrites over several hours, but may predispose to dendritic injury under extreme conditions.