CEACAM1 is a widely expressed multi-functional cell-cell adhesion protein reported to serve as a poor prognosis marker in melanoma patients. In this study we examine the functional and clinical contributions of the four splice isoforms of CEACAM1. Specifically, we present in vitro and in vivo evidence that they impact melanoma progression and immune surveillance in a negative or positive manner that is isoform-specific in action. In contrast to isoforms CEACAM1-4S and CEACAM1-4L, expression of isoforms CEACAM1-3S and CEACAM1-3L is induced during disease progression shown to correlate with clinical stage. Unexpectedly, overall survival was prolonged in patients with advanced melanomas expressing CEACAM1-3S. The favorable effects of CEACAM1-3S related to enhanced immunogenicity, which were mediated by cell surface upregulation of NKG2D receptor ligands, thereby sensitizing melanoma cells to lysis by natural killer cells. Conversely, CEACAM1-4L downregulated cell surface levels of the NKG2D ligands MICA and ULBP2 by enhanced shedding, thereby promoting malignant character. Overall, our results define the splice isoform-specific immunomodulatory and cell biological functions of CEACAM1 in melanoma pathogenesis.