Background. Higher Cathepsin D (Cath D) concentrations occur in laryngeal cancer tissues than in their normal mucosa counterpart, which suggests that Cath D could be involved also in laryngeal tumor cell growth processes was previously observed. Material and method. A total of 63 patients with primary laryngeal squamous cell carcinoma were followed up for a median of 33 months after surgery. Cath D concentration was assayed using a solid phase two site immunoradiometric assay in which the first monoclonal antibody is coated on the ELISA solid phase and the second one, M1G8 radiolabelled with I125-EGF, is used as the tracer. Results. Cath D positivity (>13.8 pM/mg prot) was closely related to neck lymph node involvement (p = 0.04) at presentation and to a short metastasis free-survival (MFS) (p = 0.005). Cox's univariate regression analysis using Cath D as a continuous variable showed that Cath D levels are correlated with the neck lymph node metastasis (p = 0.01). On multivariate analysis Cath status proved to be an independent factor for predicting a short MFS (p = 0.02). Conclusions. Cath D assay may prove to be particularly useful in identifying laryngeal cancer patients who, with or without neck lymph node involvement at presentation, are at high risk of metastatic disease and a poor outcome.