Objectives: Impaired cochlear perfusion seems to be an important event in sudden sensorineural hearing loss. Prothrombotic gene mutations have been related to vascular disorders and sudden hearing loss. We assessed the prothrombotic risk in 10 patients with sudden sensorineural hearing loss who had previously experienced cardiovascular events to support its vascular pathogenesis. Methods: Ten patients underwent hematologic tests (MTHFR C677T/A1298C, prothrombin G20210A, platelet GlyIIIaA1/A2, and V Leiden G1691A genotyping; fibrinogenemia; cholesterolemia; homocysteinemia; folatemia). The results were compared with those of 100 previously investigated patients with sudden hearing loss alone and those of 200 healthy controls. DNA was isolated from peripheral blood leukocytes, and the gene mutations were investigated by polymerase chain reaction and a LightCycler DNA analyzer. Results: Two patients had 2 mutant alleles, 6 had 3, and 2 had 4. The mean homocysteine, cholesterol, and fibrinogen levels were above the upper limit of normal; the mean folate levels were slightly above the lower limit of normal. Multiple mutations were more frequent in the patient group than in the previously analyzed patients and healthy controls. Conclusions: The association between inherited and acquired prothrombotic factors in patients with sudden sensorineural hearing loss and thrombotic diseases in other sites suggests that a multifactorial mechanism may underlie microvascular cochlear impairment. Hematologic investigation, including MTHFR, prothrombin, platelet, and V Leiden genotyping, may help to detect patients at potential risk of recurrent hearing loss and multiple microvascular diseases, and could be usefully performed in otherwise idiopathic sudden sensorineural hearing loss.