Thyroid nodules with a predominant follicular structure are often diagnosed as indeterminate at fine-needle aspiration biopsy (FNAB). We studied 453 patients with a thyroid nodule diagnosed as indeterminate at FNAB by using a feed-forward artificial neural network (ANN) analysis to integrate cytologic and clinical data, with the goal of subgrouping patients into a high-risk and in a low-risk category. Three hundred seventy-one patients were used to train the network and 82 patients were used to validate the model. The cytologic smears were blindly reviewed and classified in a high-risk and a low-risk subgroup on the basis of standard criteria. Neural network analysis subdivided the 371 lesions of the first series into a high-risk group (cancer rate of approximately 33% at histology) and a low-risk group (cancer rate of 3%). Only cytologic parameters contributed to this classification. Analysis of the receiver operating characteristic (ROC) curves demonstrated that the ANN model discriminated with higher sensitivity and specificity between benign and malignant nodules compared to standard cytologic criteria (p < 0.001). This value did not show degradation when ANN predictions were applied to the validation series of 82 nodules. In conclusion, neural network analysis of cytologic data may be a useful tool to refine the risk of cancer in patients with lesions diagnosed as indeterminate by FNAB.