Background: The response of metastatic melanoma to anti-PD1 is heterogeneous. We performed proteomic profiling of patient plasma samples to build a predictor of immunotherapy response and uncover biological insights underlying primary resistance. Methods: 58 metastatic melanoma patients receiving anti-PD1 (Pembrolizumab or Nivolumab) at MGH comprised the initial cohort, and 150 additional patients comprised a validation cohort. Plasma samples were collected (MGH IRB #11-181) at baseline and several on-treatment time-points. Samples were analyzed for 1102 proteins by a multiplex proximity extension assay (Olink Proteomics). A subset of patients had single-cell RNA-seq (Smart-Seq2 protocol) performed on tumor tissue. Group differences and treatment effects were evaluated using linear mixed models with maximum likelihood estimation for model parameters, and Benjamini and Hochberg multiple hypothesis correction. Results: 70 significantly differentially expressed (DE) proteins were identified across the treatment period, including markers of immune activation (PD1, CXCL9, CXCL10, CD25, IL-17a, among others). 38 significantly DE proteins were identified with on-treatment time points between anti-PD1 responders (R) and non-responders (NR), including several implicated in primary or acquired resistance (IL8, MIA, ERBB2, among others). Importantly, we demonstrate the relationship of these serum biomarkers to overall and progression-free survival, and employed statistical learning approaches to build classifiers of treatment response, leveraging early and late on-treatment time points. Analysis of single-cell RNA-seq data (Sade-Feldman et al, Cell, 2018) of tumor tissue from a subset of these patients revealed that gene expression of most proteins predictive of response were enriched among tumor myeloid cells, with the remainder of proteins being reflective of exhausted T cell states. Conclusions: Whole plasma proteomic profiling of anti-PD1 treated patients revealed DE proteins between R and NR that may enable a liquid biopsy to predict anti-PD1 response. These results unveil a putative role of myeloid cells within the tumor microenvironment in anti-PD1 response or primary resistance.