Objective The clinical management of patients with thyroid nodules that are biopsied by fine-needle aspiration cytology and yield indeterminate results remains unsettled. The BRAF V600E mutation has dubious diagnostic value due to its low sensitivity. Novel strategies are urgently needed to distinguish thyroid malignancies from thyroid nodules. Design This prospective study included 504 thyroid nodules diagnosed by ultrasonography from 468 patients, and fine-needle aspiration cytology was performed under ultrasound guidance. Cytology and molecular analysis, including BRAF V600E, RET/PTC1 and RET/PTC3, were conducted simultaneously. The cytology, ultrasonography results, and mutational status were gathered and analyzed together. Predictive scoring systems were designed using a combination of diagnostic parameters for ultrasonography, cytology and genetic analysis. The utility of the scoring systems was analyzed and compared to detection using the individual methods alone or combined. Result The sensitivity of scoring system(a) (ultrasonography, cytology, BRAF V600E, RET/PTC) was nearly identical to that of scoring system(b) (ultrasonography, cytology, BRAF V600E); these were 91.0% and 90.2%, respectively. These sensitivities were significantly higher than those obtained using FNAC, genetic analysis and US alone or combined; their sensitivities were 63.9%, 70.7% and 87.2%, respectively. Scoring system(c) (ultrasonography, cytology) was slightly inferior to the former two scoring systems but still had relatively high sensitivity and specificity (80.5% and 95.1%, respectively), which were significantly superior to those of single cytology, ultrasonography or genetic analysis. In nodules with uncertainty cytology, scoring system a, scoring system(b) and scoring system(c) could elevate the malignancy detection rates to 69.7%, 69.7% and 63.6%, respectively. Conclusion These three scoring systems were quick for clinicians to master and could provide quantified information to predict the probability of malignant nodules. Scoring system(b) is recommended for improving the detection rate among nodules of uncertain cytology.