Background Diagnosis of focal nodular hyperplasia (FNH) with US generally requires the use of contrast material. The effect of the super-resolution US technique on the diagnosis of FNH is unknown. Purpose To investigate the equivalence between super-resolution US and contrast material-enhanced US in the detection of spoke wheel sign in patients with FNH by comparing patterns of tumor vascularity. Materials and Methods This is a secondary analysis of a prospective trial (NCT02737865) that enrolled participants diagnosed with FNH between May 2016 and March 2019. These patients underwent super-resolution US and subsequent contrast-enhanced US with perfluorobutane microbubbles on the same day. The primary outcome was the confidence score of detecting spoke wheel sign in patients with FNH at US. Two radiologists used a four-point scale to score their confidence in the presence of the spoke wheel sign based on super-resolution US and contrast-enhanced US findings. Two one-sided tests were used to test the equivalence between super-resolution US and contrast-enhanced US in terms of the score for the confidence level of the spoke wheel sign. Interobserver agreement for both techniques between the two radiologists, using the recorded images, was analyzed by using an intraclass correlation coefficient. Results In 62 patients (mean age, 37 years; range, 20-69 years; 41 women) with FNH, the majority of patients showed a spoke wheel sign at super-resolution US and contrast-enhanced US (63% [39 of 62] and 71% [44 of 62], respectively; P = .36). There was no significant difference between the super-resolution US and contrast-enhanced US techniques regarding the confidence score for the spoke wheel sign (mean score, 1.8 vs 2.0; P = .03 for equivalence test). The intraclass correlation coefficients of super-resolution US and contrast-enhanced US regarding the presence of the spoke wheel sign were 0.82 (95% confidence interval: 0.73, 0.96) and 0.58 (95% confidence interval: 0.41, 0.73), respectively. Conclusion In comparison with contrast-enhanced US, super-resolution US provided a reliable rate of detection of the spoke wheel sign in patients with focal nodular hyperplasia. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Fetzer in this issue.