The expression of the adhesion molecule CD44 was examined in 14 primary sinonasal melanomas (SMs), aggressive neoplasms with short survival times, as CD44 overexpression has been linked to poor survival in human cancers. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections with CD44 isoform-specific monoclonal antibodies to the CD44 standard (s) and variant isoforms (v) v5 and v6. CD44s, v5, and v6 were strongly expressed in a membranous pattern in SM in situ, early invasive SM, and in uninvolved respiratory/squamous epithelium. In invasive SM, membranous CD44s expression was identified in a large proportion of melanoma cells. Membranous staining of CD44v5 and v6 was lost in invasive SM, independently of the histological subtype. Diffuse cytoplasmic staining was observed focally in invasive SM and loss of cytoplasmic expression of CD44v6 and v5 was associated with advanced tumour stage in the linear-by-linear association test (p = 0.042 and 0.066, respectively). CD44s may not be important for malignant transformation, as it is expressed in both benign and malignant melanocytes. Loss of membranous CD44 isoform expression in widely invasive SM suggests that loss of cellular adhesion facilitates matrix and vascular infiltration and dissemination of sinonasal melanoma cells.