Pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase expressed by a number of cell types, has the important role of cleaving insulin-like growth factor (IGF)-binding protein-2, -4 and -5 in the extracellular matrix and thus freeing up IGF and making it available to cells. The objective of the present study was to utilize immunocytochemical analysis to determine the proportion of PAPP-A-positive cells in a large group of disc specimens which covered the spectrum of changes from relatively healthy Thompson grade II discs to extremely degenerate grade V discs. Work was approved by our institutional human subjects review board. Seventy-two intervertebral disc specimens were assessed for immunocytochemical localization of PAPP-A and the proportion of positive cells determined in the outer annulus, inner annulus and nucleus pulposus. The percentage of PAPP-A positive cells in both the outer and inner annulus correlated significantly with increasing stages of disc degeneration in a fashion which was not dependent upon subject age. There was no significant difference in the percentage of PAPP-A positive cells in the inner annulus of herniated vs non-herniated sites, or in the outer annulus of herniated vs non-herniated sites. Data reported here point to the importance of additional work to elucidate the role of PAPP-A in intervertebral disc aging and degeneration.