The aim of this study was to verify the efficacy and the safety of transtympanic dexamethasone to treat sudden sensorineural hearing loss as first and single drug method. Considering ethical implication of performing a mininvasive procedure on middle ear, we matched such proposed treatment with systemic prednisone administration that represents the widest adopted protocol. Randomized prospective study was conducted. The inclusion criterion was a sudden sensorineural hearing loss of at least 30 dB across three contiguous frequencies over a period of 24 h. Group A received transtympanic steroid injections; Group B received oral administration of steroids. 25 patients were treated with transtympanic therapy whereas 21 underwent systemic treatment. The mean of initial PTA was 59 dB for the whole series: 65 dB for group A and 51 dB for group B. The recovery better than 10 dB was obtained in 80% of patients of group A and in 17 81% of patients of group B, with a total of 80.5%. The mean relative gain in PTA was 41.16% in the group A and 44.7% in the group B. In the frequencies tested (0.5, 1, 2, and 4 kHz) PTA improvements after transtympanic treatment were higher than after systemic treatment, but these differences were not statistically significant (P = 0.61). Both transtympanic and systemic treatment had similar clinical recovery times. This prospective randomized clinical study showed good result in terms of hearing recovery, better than the expected results of the simple observation without treatment. We can consider transtympanic administration as a first line treatment, because of the statistical analysis confirmed similar results with systemic therapy, reducing possible side effects of systemic drug administration. The delay of treatment does not influence the outcome, allowing treating patients within 10 days of onset.