Treatment for metastatic melanoma includes targeted and/or immunotherapy. Although many patients respond, only a subset has complete response. As late-stage patients often have multiple tumors in difficult access sites, non-invasive techniques are necessary for the development of predictive/prognostic biomarkers. PET/CT scans from 52 patients with stage III/IV melanoma were assessed and CT image parameters were evaluated as prognostic biomarkers. Analysis indicated patients with high standard deviation or high mean of positive pixels (MPP) had worse progression-free survival ( = 0.00047 and = 0.0014, respectively) and worse overall survival ( = 0.0223 and = 0.0465, respectively). Whole-exome sequencing showed high MPP was associated with mutation status ( = 0.0389). RNA-sequencing indicated patients with immune "cold" signatures had worse survival, which was associated with CT biomarker, MPP4 ( = 0.0284). Multiplex immunofluorescence confirmed a correlation between CD8 expression and image biomarkers ( = 0.0028). IMPLICATIONS: CT parameters have the potential to be cost-effective biomarkers of survival in melanoma, and reflect the tumor immune-microenvironment. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/6/950/F1.large.jpg.