Background: Several mechanisms are involved in the development of resistance to therapy in LACSCC. Studies have shown that CD44 and Lewis Y antigen (LeY) form a complex that is associated with chemoresistance, tumor invasion and metastasis. We assessed the role of CD44 and LeY in the outcome of LACSCC patients (pts) treated with different chemotherapy regimens. Methods: A total of 126 LACSCC pts FIGO stages IIB-IVA were selected from GOCS databases: 74 pts included in three different prospective phase II trials in the neoadjuvant setting (vinorelbine, docetaxel, ifosfamide-vinorelbine-cisplatin) and 52 pts treated with standard radio-chemotherapy based in cisplatin (RCBC). CD44 and LeY expressions were detected in pre-treated biopsy by immunohistochemistry. Clinical data at baseline, disease free survival (DFS) and overall survival (OS) were recorded. Univariate and multivariate Cox models were used to analyze variables of interest. Results: Median age was 45.6 years (range: 24.9 - 80.5). Sixty-three and 47 tumors were CD44+ and LeY+, respectively. Expansive growth tumors showed a higher grade (p= .0024), mitotic index (p= .0505), tumoral necrosis (p= .0191), LeY+ (p= .0034) and CD44+/LeY+ co-expression (p= .0334). CD44+ cells were present in 81.3% of tumors with viral cytopathic effect and in 91.3% of those with local recurrence (p= .0317). Advanced stage was associated with LeY+ (p= .0057) and CD44+/LeY+ (p= .081). In the univariate analysis, low pre-treatment hemoglobin level, expansive growth pattern, advanced FIGO stage and poor response to therapy were associated with shorter DFS and OS. Pts treated with RCBC had worse DFS and OS when their tumors expressed LeY antigen (p= .0083 and p= .0137, respectively). Pre-treatment hemoglobin level, FIGO stage and tumor response remained the most significant prognostic factors in Cox regression. Conclusions: In our cohort of LACSCC pts, the co-expression of CD44/LeY was not associated with worse outcome. However, in the subgroup of pts receiving RCBC, LeY expression was correlated with shorter DFS and OS.