ObjectivesThe main aim of this study is to evaluate the correspondence between the ultrasonographic thickness and the Breslow thickness in melanoma using ultra‐high frequency ultrasound and the intra‐ and inter‐operator repeatability in the ultrasonographic measurements of melanoma depth. Moreover, we propose a new protocol based on a combined ultrasonographic–histopathological approach.MethodsWe analyzed 27 melanomas in a population consisted of 27 patients (mean age 57.6 years, 51.8% males), who came at the Department of Dermatology (University of Pisa, Pisa, Italy) from April 2016 to March 2018 and had an ultrasonographic examination of a suspected lesion before the surgical removal using ultra‐high frequency ultrasound (Vevo®MD, Fujifilm, Visualsonics, Toronto, Canada; 70 MHz probe). B‐mode images were analyzed by two skilled and blinded operators, and the maximum depth of the lesions was measured using a dedicated graphical user interface developed in Matlab R2016b (MathWorks Inc., Natick, MA), to obtain repetitive measurements.ResultsAll melanomas appeared as band‐like or oval/fusiform shaped hypoechoic inhomogeneous lesions. We observed an excellent agreement between the Breslow thickness of melanomas and the ultrasonographic thickness, as well as a reduced intra‐ and inter‐operator variability in the ultrasonographic measurements of melanoma depth.ConclusionsWe propose a ultrasonographic–histopathological protocol which may help clinicians to reduce the diagnostic delay, improve prognosis and survival rates, perform a surgical excision with negative margins, and reduce the variability in the assessment of Breslow thickness.