Since squamous cell carcinoma antigen (SCC-Ag) testing became commercially available on the Architect platform, the previously established method on the Abbott IMx platform has been progressively replaced. Aim of this work was to compare SCC-Ag values obtained with the 2 methods. Clinical and laboratory data of 188 patients for whom SCC-Ag determination was requested, were reviewed. IMx was used to determine the levels of SCC-Ag from June 2007 to May 2009, while the Architect system was used from June 2009 to April 2011. Only patients consistently diagnosed with no evidence of disease, for whom at least 2 determinations with each analyzer were available were used. Comparison of the results obtained with the 2 systems was then performed. Mean values for SCC-Ag were 0.56 ng/mL (Standard Error (SE): 0.08) with the IMx method, and 1.08 ng/mL (SE 0.10) with Architect (p<0.0001). False positive results were found in 4.8% of patients with the IMx method and in 9.5% of patients with Architect (p=0.049). The values of SCC-Ag determined on the Architect platform are higher than those obtained on the IMx, with a higher percentage of false positive results.