Cross-sectional studies have shown plasma cell adhesion molecules (CAMs) to be increased in patients with diabetes-related complications. In the first prospective study of CAMs, we have shown that plasma CAMs may be a predictor of the development of diabetic neuropathy. We followed up 28 diabetic patients (13 neuropathic) over a 5 year period, starting from 1991. All patients had peroneal nerve conduction velocity (PNCV), vibration perception threshold and plasma CAMs measured at baseline and follow-up. We found P-selectin and intercellular adhesion molecule-1 (ICAM-1) to be increased at baseline in patients with neuropathy compared to non-neuropathic patients. P-selectin and E-selectin were also found to be significantly higher at baseline in patients who at follow-up showed deterioration in PNCV of more than 3 m/s (p<0.05; p=0.01; respectively). P-selectin and ICAM-1 strongly correlated with PNCV. Univariate and multivariate regression analyses showed a significant inverse association between increasing log P-selectin, log E-selectin and log ICAM-1 with decreasing PNCV, and remained significant even after adjustment for glycaemic control. P-selectin and E-selectin, odds ratios of 8.8 (95% CI: 1.1-68.8; p=0.038) and 12.5 (95% CI: 1.2-132.1; p=0.036), respectively, were significantly associated with the risk of deterioration of PNCV after 5 years. This study suggests that plasma cell adhesion molecules may play an important role in the development and progression of peripheral neuropathy in diabetes mellitus.