Hyperviscosity, due to alterations of blood cells and plasma components, can induce microvascular damage. Nitric oxide (NO) is released by endothelium and plays a crucial role in flow-mediated vasodilation. An impaired availability of NO, due to polymorphisms of endothelial NO synthase (eNOS), may influence erythrocyte deformability thus increasing blood viscosity. We investigated haemorheological variables in patients with idiopathic sudden sensorineural hearing loss (ISSHL), retinal vein occlusion (RVO) and systemic sclerosis (SSc), as possible models of microvascular damage, and their relationship with eNOS gene T-786C, G894T and 4a/4b polymorphisms. Whole blood viscosity and plasma viscosity were assessed with a rotational viscosimeter and erythrocyte deformability index (DI) with Myrenne filtrometer. eNOS polymorphisms were analyzed in ISSHL and SSc patients. At multivariate analysis alterations of some haemorheological variables resulted significantly associated with ISSHL, RVO and SSc. A significantly higher prevalence of eNOS -786C and 894T was found in both ISSHL and SSc patients than in controls; at multivariate analysis these two polymorphisms significantly affected DI in both groups of patients. These results suggest that hyperviscosity, either determined by genetic susceptibility or not, can be involved in the pathophysiology of these clinical disorders and can be the target of new therapeutic strategies.