Objective: The basis of thyroid nodule diagnostics is ultrasound guided fine needle biopsy with cytological evaluation (FNC), if US appearance is not clearly benign. The aim of this study was to investigate the predictive potential of dedicated, expert high resolution ultrasound, to see if histopathological entities of thyroid nodules can be diagnosed without invasive FNC biopsies. Design: Prospective case cohort study. Methods: 180 patients with 221 thyroid nodules were examined with ultrasound and prospectively assigned to the expected histopathological diagnosis: colloid nodule, adenomatoid colloid nodule, follicular adenoma, follicular carcinoma, follicular variant of papillary thyroid carcinoma, papillary thyroid carcinoma, or other thyroid cancer. In 101 of these, we later obtained histopathological reports for comparison. Results: Overall accuracy for classification into discrete histopathological categories by expert ultrasound was 71.3% and Cohen’s Kappa was 0.62. The sensitivity and specificity for detecting malignancy was 97.3% and 78.1%. The diagnostic accuracy for malignancy was 85.1%. ACR-TIRADS scores for the same nodules had a sensitivity of 97.3%, specificity of 26.6%, and accuracy of 52.5%. Conclusion: Dedicated expert high-resolution ultrasound without FNC can reliably distinguish benign versus malignant nodules, but also differentiate between several histopathological entities in thyroid nodules. There is potential for a reduction in the number of invasive FNC biopsies and diagnostic operations.