Study Design. This study is an in vitro investigation of the effects of substance P on intervertebral disc cell metabolism. Objectives. To determine whether the neuropeptide, substance P, affects cells isolated from the intervertebral disc. Summary of the Background Data. Nerve fibers containing substance P are present in the anulus fibrosus and may be released from the nerve terminals as in other tissues. Substance P is mitogenic for a variety of immune and connective tissue cells, and a fragment of the peptide affects the metabolism of articular chondrocytes. Methods. Cells were isolated enzymically from the anulus fibrosus of intervertebral disc of 8-week-old rabbits. The effects of substance P and the C-terminal pentapeptide fragment SP7-11 on cell proliferation and proteoglycan deposition were determined by crystal violet and Alcian blue staining, respectively. Results. Substance P (10(-11)-10(-7) mol/l) had a small stimulatory effect on disc cell proliferation. Proteoglycan deposition in the cell layer increased concomitantly. A greater proliferative effect was observed with substance P fragment 7-11 or with the addition of the neutral endopeptidase inhibitor, phosphoramidon. Conclusions. Substance P has small mitogenic effects on rabbit intervertebral disc cells in vitro. Further investigation is required to establish whether this might have biologic relevance in relation to the maintenance or repair of the intervertebral disc.