Some amphibian retinal ganglion cells die during optic nerve regeneration. Here we have investigated whether ganglion cell death in the frog Litoria moorei is associated with the lesion site. For one experimental series, the optic nerve lesion extended for 0.15 mm; in the other, it extended for 1.5 mm. The extent of ganglion cell death was estimated from cresyl violet-stained whole mounts at 24 weeks post lesion. In other animals, individual regenerating axons were visualised in the optic nerve by horseradish peroxidase (HRP) labelling from 1 day to 24 weeks post lesion; counterstaining with cresyl violet allowed examination of cells that repopulated the lesion site. Ganglion cell numbers fell significantly more after an extensive than after a localised lesion, long-term losses being 50% and 34%, respectively (P <0.05). Regenerating axons were delayed in their passage across the cell-poor extensive lesion compared with the relatively cell-rich localised lesion. The differing rates of regeneration between series were matched by greater delay after extensive lesion in the return of visually guided behaviour as assessed by optokinetic horizontal head nystagmus. We suggest that delays in regeneration after an extensive lesion exacerbate ganglion cell death, indicating that conditions within the lesion are associated with the death of some ganglion cells. (C) 2002 Wiley-Liss, Inc.