We enrolled 42 patients with metastatic NSCLC before and during anti-PD-1 treatment, evaluating circulating levels of different autoantibodies and Peripheral Blood Mononuclear Cells (PBMCs) populations….The presence of IgM-Rheumatoid Factor (IgM-RF) in patients sera was strongly associated (OR, 7,66; 95% CI, 1.62 to 36.18; p=0.005) with the development of early progression. IgM-RF positivity resulted also as an important prognostic factor for a worse outcome in terms of both PFS (p=0.035) and OS (p=0.034), with a more marked reduction of PFS rate (p=0.002) identified when patients were further stratified based on IgM-RF titers....IgM-RF can be ascribed as a novel biomarker that is able to predict the development of early progression and, in addition, as a prognostic factor for a reduced PFS and OS in NSCLC patients in treatment with anti-PD-1 ICIs.