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Background: The liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases have been associated with a more favorable outcome. There are limited data available regarding the immune microenvironment at different anatomical sites of melanoma metastases. This study sought to characterize and compare the tumor immune microenvironment of liver, brain, lung, subcutaneous (subcut) as well as lymph node (LN) melanoma metastases., Methods: We analyzed OS in 1924 systemic treatment-naïve patients with AJCC (American Joint Committee on Cancer) stage IV melanoma with a solitary site of organ metastasis. In an independent cohort we analyzed and compared immune cell densities, subpopulations and spatial distribution in tissue from liver, lung, brain, LN or subcut sites from 130 patients with stage IV melanoma., Results: Patients with only liver, brain or bone metastases had shorter OS compared to those with lung, LN or subcutaneous and soft tissue metastases. Liver and brain metastases had significantly lower T-cell infiltration than lung (p=0.0116 and p=0.0252, respectively) and LN metastases (p=0.0116 and p=0.0252, respectively). T cells were further away from melanoma cells in liver than lung metastases (p=0.0335). Liver metastases displayed unique T-cell profiles, with a significantly lower proportion of programmed cell death protein-1+ T cells compared to all other anatomical sites (p<0.05), and a higher proportion of TIM-3+ T cells compared to LN (p=0.0004), subcut (p=0.0082) and brain (p=0.0128) metastases. Brain metastases had a lower macrophage density than subcut (p=0.0105), liver (p=0.0095) and lung (p<0.0001) metastases. Lung metastases had the highest proportion of programmed death ligand-1+ macrophages of the total macrophage population, significantly higher than brain (p<0.0001) and liver metastases (p=0.0392)., Conclusions: Liver and brain melanoma metastases have a significantly reduced immune infiltrate than lung, subcut and LN metastases, which may account for poorer prognosis and reduced immunotherapy response rates in patients with liver or brain metastases. Increased TIM-3 expression in liver metastases suggests TIM-3 inhibitor therapy as a potential therapeutic opportunity to improve patient outcomes., Competing Interests: Competing interests: MSC reports personal fees from BMS, Merck Sharp & Dohme, Novartis, Roche, Amgen, Pierre-Fabre and Ideaya. RPMS has received honoraria for advisory board participation from MSD, Novartis and Qbiotics and speaking honoraria from BMS and Novartis. JFT has received honoraria for advisory board participation from BMS Australia, MSD Australia, GSK and Provectus, and travel and conference support from GSK, Provectus and Novartis. AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre and QBiotics. GVL is consultant advisor for Agenus Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA Inc, Merck Sharpe & Dohme (Australia) Pty Limited, Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec Medical Australia, PHMR Limited, Pierre Fabre, Provectus Australia, Qbiotics Group Limited, Regeneron Pharmaceuticals Inc. RAS has received fees for professional services from F. Hoffmann-La Roche, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, Amgen, Bristol Myers Squibb, Myriad Genetics and GlaxoSmithKline. IPS had travel support by BMS and MSD, and speaker fee by Roche, Bristol Myers Squibb and Merck Sharpe & Dohme. All remaining authors declared no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)