Background: Uveal melanoma (UM) is a rare subset of melanoma that is resistant to immune checkpoint blockade. High density of macrophages (Mϕ) and TILs is associated with poor prognosis in primary UM but little is known about the tumor microenvironment (TME) in metastatic UM (MUM). Here we performed quantitative spatial analysis using multiplex immunohistochemistry (mIHC) to characterize the TME in MUM, compare the TME of MUM to metastatic cutaneous melanoma (MCM), and identify potential mechanisms of MUM resistance to immunotherapy. Methods: We identified pts with untreated metastatic melanoma with clinical follow-up and available pre-treatment tissue who consented to an IRB-approved protocol. 5µm slides were stained using Opal mIHC for DAPI, CD3, CD8, CD68, HLA-DR, Ki67, and SOX10. Tumor areas were pre-selected by a dermatopathologist, visualized using Vectra and analyzed for density and spatial localization using inForm software. Results: 6 MUM and 8 MCM cases were evaluable at the time of this analysis. CD3+ and CD8+ T-cell density is similar between MUM and MCM, however, there is a trend towards a higher density of proliferating cytotoxic T lymphocytes (CTL) (CD8+Ki67+) in MCM (p = 0.05). Interestingly, CD68+ Mϕ density is lower in MUM compared to MCM (p = 0.03). Both CD68+HLA-DR+ Mϕ (activated) and CD68+HLA-DR- Mϕ (inactivated) density is lower in MUM. Using nearest neighbor spatial analysis, CD8+ CTLs are significantly farther from activated Mϕ (CD68+HLA-DR+) (p = 0.01), but not from inactivated Mϕ (CD68+HLA-DR-) in MUM compared to MCM. Conclusions: Unlike primary UM, our sample of untreated MUM is not characterized by a high Mϕ density. Fewer Mϕ are present in untreated MUM compared to MCM and activated Mϕ are located farther from CTLs in UM. Density of CTLs is similar in MUM and MCM, although proliferating CTL are more numerous in MCM. These preliminary results suggest that Mϕ may play a less prominent role in innate resistance to immunotherapy in MUM. Gene expression analysis and further classification of Mϕ type is ongoing. Additional cases are ongoing analysis and will be reported.