Background: Immune checkpoint inhibitors have significantly improved melanoma (MEL) patient (PT) outcomes. Immune-related adverse events (irAEs) may cause significant morbidity, rarely including death. Soluble immune checkpoints have been identified as biomarkers of autoimmune activity and potential off-target pathology. Understanding their relationship to pathologic outcomes may assist in the identification of PTs at highest risk of irAEs. Methods: PTs with resectable stage IIB-IV MEL who received adjuvant anti-programmed-death-1 (PD-1) therapy were identified from the University of Pittsburgh’s MEL Center biospecimen repository (N=273). MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel 2 was used to study serum levels of immunomodulatory proteins. Mean pretreatment serum levels in PTs with and without irAEs were compared using a two-sample t-test after performing Box-Cox transformation for non-normally distributed data. Results: Sera from 43 PTs were analyzed. The cohort included 28 (65.1%) male, mean age at diagnosis (62), including MEL stage IIIA = 7 (16.3%), IIIB = 16(37.2%) and IIIC = 20(46.5%). The most common irAEs (n=24, 55.8%) were thyroiditis (n=9, 20.9%), dermatitis (n=8, 18.6%), and adrenal insufficiency (n=9, 21.0%). Multiple irAEs were observed amongst 22 (51.2%) PTs with ≥3 irAEs and 6 (13.9%) with 5 irAEs. Visceral irAEs included Hepatitis (n=3, 7.0%), pneumonitis (n=2, 4.7%), and colitis (n=5, 11.6%). Seven of 8 patients with visceral irAEs required corticosteroids. Siglec-7 (mean 23.4 vs 3.51 pg/mL, p=0.018) and siglec-9 (mean 77.0 vs 33.1 pg/mL, p=0.049) were significantly elevated in the PTs who developed any irAE. After stratifying for each individual irAE, PTs with thyroiditis had elevated Nectin-4 (mean 2785.5 vs 494.7 pg/mL, p<0.001) and serum arginase (mean 2437.5 vs 1383.1 pg/mL, p= 0.046) was elevated in PTs who developed colitis. PTs with hepatitis demonstrated increased galectin-3 (mean 10103.9 vs 9915.3 pg/mL, p=0.045) and decreased levels of CD40L (mean 2869.2 vs 9496.9 pg/mL, p=0.033). In PTs with dermatitis B7-H3 (mean 2503.3 vs 732.4 pg/mL, p=0.009) and MHC class I polypeptide-related sequence B (mean 1598.0 vs 259.1 pg/mL, p=0.048) were elevated. Conclusions: We have demonstrated unique serum checkpoint protein profiles related to specific irAEs in melanoma patients receiving adjuvant anti-PD1. Further studies are warranted to confirm and validate the utility of these irAE predictors during adjuvant anti-PD-1.