P53 is a key regulator of genomic stability and function, acting as a tumor suppressor protein. Our aim was to correlate P53 expression with murine double minute 2 (MDM2), a proto-oncogene that interacts with P53 and forms an auto-regulatory pathway, in laryngeal squamous cell carcinoma (LSCC). A total of 50 LSCC cases were included in the study. Immunohistochemistry was applied by using antibodies to P53 and MDM2 in the corresponding tissue sections. Protein expression levels for both molecules were measured by implementing a digital image analysis assay (immunostaining intensity levels, densitometric evaluation). Overexpression of P53 protein was observed in 16/50 (32%) LSCC cases, while 22/50 (44%) cases strongly expressed MDM2 protein. Interestingly, in 13/50 (26%) cases, combined overexpression of P53/MDM2 was detected. Overall P53 was strongly positively correlated with MDM2 expression (p=0.001). Both P53 and MDM2 overexpression were significantly correlated with advanced stage of LSCC (p=0.032 and p=0.001, respectively). Additionally, MDM2 was found to be associated with poorer survival of patients (p=0.046). Aberrant co-expression of P53 and MDM2 is associated with advanced stage in LSCC. Furthermore, MDM2 overexpression is a frequent and critical genetic event in LSCC and seems to negatively affect survival.