Real-time elastography has been proposed to increase the sensitivity of ultrasound and improve the detection of thyroid nodules at risk of malignancy. To date sparse data on real-time elastography assessment of autonomously functioning thyroid nodules exist. Here, we investigated the potential role of real-time elastography in autonomously functioning thyroid nodule assessment. Specifically, the correlation between serum hormones and real-time elastography score, as well as other clinical and ultrasound features, was analyzed. Patients with autonomously functioning thyroid nodule identified by I-123 scintigraphy from September 2015 to July 2016 and undergoing ultrasound, real-time elastography, and thyroid function evaluation were selected. All autonomously functioning thyroid nodule were classified as RTE I (prevalence of red or green color with blue in up to 25% of the nodule area), RTE II (blue in 25-75%), or RTE III (blue in more than 75%). The association between suppressed thyroid stimulating hormone and patient's age, nodule's size, ultrasound presentation, and real-time elastography scoring was analyzed by Odds Ratio in univariate fashion and multivariate model. A number of 47 subjects with single autonomously functioning thyroid nodule were enrolled. Median age of 63 years, median size of 2.0 cm, and suppressed thyroid stimulating hormone levels in 32% of cases were found. Those nodules classified by ultrasound at high risk underwent fine-needle aspiration cytology and cancer was excluded. At real-time elastography evaluation, a 45% of autonomously functioning thyroid nodule had a hard appearance (RTE III) and had thyroid stimulating hormone significantly lower than the other (p < 0.0001). A model of multivariate logistic regression including nodule's size, ultrasound characteristics, and elastographic presentation showed that only RTE III was significantly associated with suppressed thyroid stimulating hormone (Odds Ratio of 50). Autonomously functioning thyroid nodule may have variable elasticity at real-time elastography examination, being hard score associated with reduced/suppressed thyroid stimulating hormone. For clinical practice, the presence of autonomously functioning thyroid nodule should be considered in patients with hard lesions. Also, as quoted by the most recent ATA guidelines, elastography should not be accounted for risk stratification of thyroid nodules.