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Fine-needle aspiration biopsies (FNA) represent the gold standard to exclude the malignant nature of thyroid nodules. After cytomorphology, 20–30% of cases are deemed “indeterminate for malignancy” and undergo surgery. However, after thyroidectomy, 70–80% of these nodules are benign. The identification of tools for improving FNA’s diagnostic performances is explored by matrix-assisted laser-desorption ionization mass spectrometry imaging (MALDI-MSI). A clinical study was conducted in order to build a classification model for the characterization of thyroid nodules on a large cohort of 240 samples, showing that MALDI-MSI can be effective in separating areas with benign/malignant cells. The model had optimal performances in the internal validation set (n = 70), with 100.0% (95% CI = 83.2–100.0%) sensitivity and 96.0% (95% CI = 86.3–99.5%) specificity. The external validation (n = 170) showed a specificity of 82.9% (95% CI = 74.3–89.5%) and a sensitivity of 43.1% (95% CI = 30.9–56.0%). The performance of the model was hampered in the presence of poor and/or noisy spectra. Consequently, restricting the evaluation to the subset of FNAs with adequate cellularity, sensitivity improved up to 76.5% (95% CI = 58.8–89.3). Results also suggest the putative role of MALDI-MSI in routine clinical triage, with a three levels diagnostic classification that accounts for an indeterminate gray zone of nodules requiring a strict follow-up.