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Despite the use of sentinel node biopsy techniques, the search continues for other strategies to improve the accuracy of estimating prognosis in melanoma patients. Various biomarkers have previously been studied for use in this role, but none has yet achieved acceptance in routine practice. We have applied the novel technology of tissue microarray for the high throughput screening of a cohort of 120 primary cutaneous melanoma specimens for expression of the transmembrane glycoprotein CD44, splice variant 3 (v3), which has previously been implicated in tumor progression. A highly significant correlation between CD44v3 expression and Breslow thickness, Clark's level and patient age was demonstrated (Spearman correlationp< 0.001). Regarding clinical outcome, CD44v3 expression was shown to be significantly associated with better outcome (χ2 = 7.2219,p= 0.0072). Furthermore, subgroup analysis revealed a sequentially improved survival probability associated with the intensity of CD44v3 staining (χ2 = 12.5162,p= 0.0058). Analysis in a Cox multivariate model, however, did not show CD44v3 to be independently predictive of prognosis. The implications of these findings are considered, and the use of CD44v3 as a potential prognostic marker or a target for therapeutic manipulation are discussed.