In a previous study we demonstrated that a 1-yr treatment with L-T4 induces substantial nodule volume reduction (> or = 50%) in approximately 40% of patients with a benign solitary cold thyroid nodule. The present prospective study investigated whether it is possible to identify, before starting L-T4 treatment, nodules with a high probability to shrink in response to L-T4. We recorded several clinical and cytological features in a continuous series of 42 patients with a cold nodule and related them to the nodule volume response to 1-yr treatment with L-T4. Fisher discriminant analysis showed that a combination of some cytological features (colloid, degenerative changes, cellular hyperplasia, and fibrosis) and initial nodule volume can be used for predicting nodule volume reduction. In fact, although only 33% of all nodules shrank, 62% of colloid nodules and 57% of small degenerative nodules shrank. None of the hyperplastic or fibrotic nodules shrank. These results were validated in a different retrospective series of 46 patients and allowed us to predict nodule reduction in over 80% of the cases.