Recent experiments have shown that in patients with psoriasis, highly elevated levels of nitric oxide (NO) are released at the surface of psoriatic plaques. Nitric oxide is a central biological regulator of many aspects of physiology, and it is a natural possibility that the high nitric oxide levels in psoriasis play a causal role in the onset of the disease. Here, we use mathematical modelling to investigate this possibility. We begin by discussing a simple model consisting of a single equation for nitric oxide concentration, which enables nitric oxide secretion rates in the basal epidermis to be calculated from the observed NO release rates at the skin surface. Using this key parameter value, we then develop an extended model that tests the hypothesis that nitric oxide regulates the formation of the extended rete pegs seen in psoriatic plaques. This occurs via the peroxynitrite-dependent activation of the collagenase MMP-8, which is produced by neutrophils present at high levels in psoriatic plaques. The plausibility of the hypothesis is demonstrated and specific testable quantitative predictions about the roles of the various cell types and signalling molecules are made. © 2002 Academic Press.