The success of immune checkpoint inhibitors (ICI) in melanoma therapy has catalyzed the introduction of ICI in increasingly early stages of the disease. This exposes many patients with a lower risk of relapse to the risk of protracted adverse events, highlighting the need for biomarkers guiding the use of ICI. Already many years ago, brisk infiltration of primary melanomas by lymphocytes has been linked to improved patient outcome, but controversial findings due to a high variability in classification systems have been described CD8+ T cells have been identified as a primary mediator of antitumor immunity in patients treated with ICI. As CD8+ T cells require the presentation of antigens via MHC-I on target cells, downregulation and loss of MHC-I have been observed as resistance mechanisms to ICI. In this study, we revisit the role of MHC-I expression and CD8+ T-cell infiltration in melanoma evolution using a cohort of advanced primary and matched metastatic melanomas by using an automated immunohistochemistry and digital pathology workflow. Our results show that downregulation of MHC-I expression is a frequent event in advanced primary melanomas that is associated with decreased CD8+ T-cell infiltration and an early metastatic spread to sentinel lymph nodes. Furthermore, MHC-I downregulation and decreased infiltration with CD8+ T cells are also associated with resistance to ICI. Our results suggest that analyses of MHC-I expression and CD8+ T-cell infiltration patterns could serve as future biomarkers to guide the decision to treat patients in early stages of melanoma with ICI.