As effective melanoma treatments have become available, utilizing isolated limb perfusion (ILP) to treat unresectable melanoma limited to the limb has decreased. However, some patients still receive long-term benefits from ILP. We aimed to identify features of the pretreatment tumor microenvironment (TME) to identify patients who may benefit from ILP. Pretreatment metastatic melanoma samples from 22 patients treated at Helsinki University Hospital with ILP from 2008 to 2018 were analyzed with multiplex immunohistochemistry (mIHC) and digital image analysis. Antibody panels evaluated the proportions of immune cells in the intratumoral and extratumoral compartments. We examined whether treatment response and median progression-free survival (PFS) after ILP correlated to findings in the TME. A statistically significant positive correlation was found between PFS and lower immune cell infiltrations in the intratumoral compartment (CD3+, CD4+, and CD11c+ cells), and increased numbers of immune cells in the extratumoral compartment were associated with longer PFS (CD3+, CD4+, CD8+, all expressing PD-1). Furthermore, the distribution of some immune cell subsets correlated with complete treatment response (PD-1/PD-L1-positive CD4+ and PD-1-positive CD8+ cells). Our results suggest that patients may have a better ILP outcome if the metastases exhibit a lower distribution of specific immune cell subtypes intratumorally and a higher extratumoral distribution of some immune cell subtypes.