In contrast to mammals, fish are distinguished by their enormous potential for brain repair after injuries. This phenomenon has been well studied after application of stab-wound lesions to the corpus cerebelli, a cerebellar subdivision, in the teleost fish Apteronotus leptorhynchus. By combining this lesion paradigm with immunohistochemical staining, we examined the potential role of the calcium-binding protein calbindin-D 28k in the process of regeneration. Calbindin-D 28k-immunoreactive cell bodies and fibers were evident in the lesion path and the immediate vicinity of the lesion in the period between 16 h and 7 days after the lesion but absent from this region at shorter or longer postlesion survival times and in the intact brain. Both the number of immunolabeled cells and the intensity of the label were most pronounced 1–3 days postlesion. Analysis of the morphology of the immunostained cells by confocal microscopy suggested that most, and perhaps all of them, were granular neurons. Since the transient upregulation of calbindin-D 28k is paralleled by a decline in the number of cells undergoing apoptotic cell death, we hypothesize that this protein exerts a neuroprotective function, probably by buffering free intracellular Ca 2+, whose concentration is elevated after brain insults.