XIAP up-regulation is associated with chemotherapy resistance. Phenoxodiol causes XIAP degradation and chemotherapy sensitization in ovarian cancer. Here we assessed XIAP expression in melanomas, using tissue microarrays containing 436 melanomas and 336 nevi by a novel method of automated, quantitative analysis (AQUA). We used S100 to define pixels as melanoma (tumor mask) within the array spot, and measured XIAP expression using Cy5-conjugated antibodies within the mask. XIAP expression was significantly higher in melanomas than nevi (P < 0.0001), and higher in metastatic than primary lesions (P < 0.0001). We then assessed a panel of melanoma cell lines for XIAP expression, and found high expression in all cell lines. Three of the cell lines were assessed for Phenoxodiol and Carboplatin sensitivity; all were resistant to Carboplatin and showed variable sensitivity to Phenoxodiol. Pre-treating Phenoxodiol sensitive cells with Phenoxodiol prior to Carboplatin resulted in XIAP degradation, associated with Carboplatin sensitization and apoptosis, whereas exposing Phenoxodiol resistant cells to Phenoxodiol resulted in less XIAP degradation and minimal Carboplatin sensitization. We conclude that XIAP levels in clinical specimens are significantly higher in melanomas than their benign counterparts, and higher in metastatic than in primary specimens, suggesting an association with malignant progression and disease aggression. Melanoma resistance to Carboplatin is possibly due to XIAP over-expression. Phenoxodiol can sensitize melanoma cells to Carboplatin in vitro with corresponding XIAP degradation, although the precise target and mechanism of action of Phenoxodiol are subject to further assessment. Targeting XIAP warrants additional investigation as a therapeutic approach for metastatic melanoma.