Substance P (SP) immunoreactivity was demonstrated using the indirect immunofluorescence technique in one normal and one retinoblastomatous human retina. In the normal retina SP immunoreaction was located in nerve fibres but not in the neurons in the inner plexiform layer. A similar location was observed in the histologically normal areas of the retinoblastoma sample. SP immunoreactive neurons, probably amacrine cells, were, however, observed in the transitional area between the normal retina and the tumour. The tumour mass, although mainly SP negative, contained clusters of pleomorphic cells with an intense SP immunoreaction. The general distribution of SP immunoreaction in human retina resembles that of other mammals. The positive SP immunoreaction in retinoblastoma cells suggests that the tumour either may have its origin in the amacrine cells or that the retinoblasts are capable of redifferentiating in the direction of the amacrine cell population. The general problems concerning the origin and pathogenesis of retinoblastoma are discussed.