Due to the current increased interest in the significance of the systemic inflammatory indices SII and SIRI as prognostic and predictive factors in many malignant diseases, our study focused on their simultaneous evaluation with a set of circulating biomarkers involved in different signaling pathways that have a major role in melanoma progression, such as the pro-inflammatory cytokines IL-6 and TNF-α, S100, and LDH. Here, S100B is linked to melanoma.