Plasma viscosity and erythrocyte deformability play a key role in maintaining and regulating microcirculation. In vitro and in vivo studies suggested a role for nitric oxide (NO) in modulating flow-mediated vasodilatation and red blood cell deformability. Impaired NO availability due to mutations in eNOS gene might contribute to the altered haemorheologic state. The aim of this study was to investigate the role of eNOS T-786C, G894T, and 4a/4b polymorphisms in modulating the haemorheologic state in a clinical condition characterized by a microcirculatory disorder. Eighty patients with idiopathic sudden sensorineural hearing loss (ISSHL) and 80 healthy subjects were studied. By using a dominant model of inheritance, we found a significant association between eNOS 894T rare variant and ISSHL (odds ratio [OR] 894TT+GT = 2.08, p = 0.03) after adjustment with traditional vascular risk factors. A higher percentage of altered red cell deformability both in patients and in controls carrying the eNOS rare variants was found in comparison to subjects carrying the wild type. Apart from the disease, eNOS T-786C and G894T polymorphisms independently affected the deformability index (OR, -786CC+TC = 2.81, p = 0.01 and OR, 894TT+GT = 2.5, p = 0.02, respectively), in particular in subjects in whom the contemporary presence of the two rare alleles was observed (OR, -786CC+TC and 894TT+GT combined genotype = 6.9, p<0.0001). Our study documented that eNOS gene affects the red blood cell deformability, so possibly contributing to ISSHL, which may represent a suitable model of microcirculatory disorder.