PURPOSE: In primary squamous cell carcinoma of the larynx (LSCC), Ca(2+) binding S100A2 protein underexpression was already found to be associated with poor tumour differentiation and shorter overall survival. In the present work, the role of S100A2 protein expression in the prediction of regional metastasis-free survival (MFS) was investigated to guide neck management in LSCC. EXPERIMENTAL DESIGN: Specimens of LSCC from 62 consecutive untreated patients were examined for S100A2 content by immunocytochemistry; the patients were followed up for a median of 44 months (range 2-90 months) after initial surgical resection. MFS was calculated from the date of first surgery to that of regional neck node recurrence. RESULTS: S100A2 was detected in 18 of 19 (95%) low-grade tumours and in 22 of 43 (51%) high-grade tumours. The 5-year regional MFS was 81% for patients with S100A2-positive tumours and 55% for patients with S100A2-negative tumours. By multivariate analysis, the S100A2 status appeared to be a significant independent predictive factor for MFS (p = .02). CONCLUSIONS: Our results suggest that the assessment of S100A2 status at diagnosis may identify a subset of LSCC patients highly susceptible to neck node metastases and may thus help define therapy accordingly.