Abstract Purpose Reported outcomes of postoperative radiotherapy (PORT) for laryngeal squamous cell carcinoma (LSCC) have varied and sometimes been disappointing. The aim of the present preliminary study was to investigate whether a given immunohistochemical pattern of Maspin expression in laryngeal carcinoma cells could be prognostically associated with response to PORT. Materials and Methods Thirty-two consecutive patients treated for LSCC with primary surgery and PORT. The subcellular (nuclear vs non-nuclear) pattern of Maspin expression was assessed immunohistochemically on LSCC surgical specimens and analyzed in relation to recurrence rate (RR) and disease-free survival (DFS). Results A non-nuclear Maspin expression was found in 23 of 32 cases (72%), and all recurrences (17 cases) occurred in this subgroup of patients. A non-nuclear Maspin expression was strongly associated with recurrence p = 0.0002, hazard ratio (HR) 5.58 and a shorter DFS (p = 0.0004) after PORT for LSCC. Even in N0 patients, a non-nuclear Maspin expression was associated with a significantly higher RR (p = 0.04, HR 1.42) and a shorter DFS (p = 0.02). Among the common clinic-pathological parameters considered, only N stage showed a trend toward an association with prognosis in terms of DFS (p = 0.08). Conclusion Assessing subcellular patterns of Maspin expression in LSCC specimens could identify patients less likely to respond to PORT, who might benefit from combined chemo-radiotherapy to improve the efficacy of adjuvant protocols.